No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Leptin, adiponectin, resistin, and ghrelin - Implications for inflammatory bowel disease
Abstract
Inflammatory bowel disease (IBD) is characterized by anorexia, malnutrition, altered body composition, and development of mesenteric white adipose tissue (WAT) hypertrophy. Increasing evidence suggests that adipokines synthesized either in WAT or in immune cells, are involved in these manifestations of IBD. Among adipokines leptin, adiponectin and resistin hold a fundamental role while the role of ghrelin in inflammation is not well established. Preliminary studies have shown overexpression of leptin, adiponectin, and resistin in mesenteric WAT of patients with Crohn's disease (CD) and significant alterations of circulating serum levels of these adipokines in IBD. It has also been demonstrated that intestinal inflammation causes an increase in endogenous ghrelin production. In animal models of intestinal inflammation, existing data suggest that leptin, adiponectin, and resistin are pivotal mediators of inflammation. Interesting therapeutic interventions based on these data have been suggested. A specific role for hypertrophic WAT has also been implicated in CD. Further efforts with experimental and clinical studies are needed to better understand the role of adipokines in IBD.
... White fat-produces adipokines such as adiponectin (a member of the TNF-α superfamily) and leptin [24]. Adiponectin circulates at high levels in the blood stream and is associated with increasing insulin sensitivity, decreasing gluconeogenesis and increasing glucose uptake [25]. ...
... Adiponectin circulates at high levels in the blood stream and is associated with increasing insulin sensitivity, decreasing gluconeogenesis and increasing glucose uptake [25]. Adiponectin has been shown to have anti-inflammatory properties [24] and in obesity, adiponectin levels fall as BMI increases [26]. Leptin is a member of the type 1 cytokine superfamily and is produced in direct proportion to the amount of adipose tissue [27]. ...
... Ghrelin binds to the growth hormone secretagogue receptor, stimulates increased food intake and promotes weight gain, and is increased during fasting and negative energy balance situations [32]. Ghrelin may also have anti-inflammatory properties, with inhibition of inflammatory cytokines [24]. It can be seen that adiponectin, leptin and ghrelin are modulators of energy homeostasis and also have immunomodulatory effects. ...
Objective:
Curcumin is a naturally occurring polyphenol derived from tumeric that has been reported to have anti-inflammatory properties with effects on adipokine and ghrelin levels. Adiponectin, leptin and ghrelin modulate energy homeostasis but each have modulatory effects on inflammatory cytokines and the immune system. Therefore this analysis was performed to investigate the effect of curcumin on adiponectin, leptin and ghrelin.
Methods:
A double blind randomised control trial comparing curcumin 1000mg with 10mg of piperine daily to placebo over a 12 week period. 118 patients with type 2 diabetes were recruited of whom 50 control and 50 active subjects completed the trial. Adiponectin, leptin, ghrelin and tumor necrosis factor-α (TNF-α) were measured at baseline and 12 weeks.
Results:
Between group comparison of the magnitude of changes showed serum levels of leptin (p<0.001), TNF-α (p<0.001) and leptin:adiponectin ratio (p<0.001) to be significantly reduced while serum adiponectin levels were elevated in the curcuminoids versus placebo group (p=0.032). Changes in serum ghrelin levels did not differ between the study groups (p=0.135). These effects remained statistically unaltered after adjustment for baseline values or changes in BMI. However, serum ghrelin levels were found to be significantly elevated following curcuminoid supplementation after adjustment for baseline ghrelin concentrations (p=0.017) or changes in BMI (p=0.025).
Conclusion:
Curcumin supplementation increased adiponectin, whilst the the leptin:adiponectin ratio (a measure of atherosclerosis) and leptin levels were decreased independent of weight change and reflected a decrease in the inflammatory TNF-α levels.
... The SP gut microbial modulating properties have been attributed to its high levels of phenolic bioactive, free amino acids, and nitrogenous compounds [71,73]. Another mechanism by which SP affects intestinal health may be related to regulating adipokines [74][75][76]. In vitro, in vivo, as well as human models have proposed an interconnected and complex role for leptin, ghrelin, and resistin as pivotal mediators of pro-inflammation that may trigger UC [75,77,78]. ...
... Another mechanism by which SP affects intestinal health may be related to regulating adipokines [74][75][76]. In vitro, in vivo, as well as human models have proposed an interconnected and complex role for leptin, ghrelin, and resistin as pivotal mediators of pro-inflammation that may trigger UC [75,77,78]. In a mouse model study, Fujimoto et al. [79] reported that SP was associated with significantly lower leptin concentration. ...
Aim
We conducted a randomized placebo-controlled trial to assess the efficacy of Spirulina (SP) supplementation on disease activity, health-related quality of life, antioxidant status, and serum pentraxin 3 (PTX-3) levels in patients with ulcerative colitis (UC).
Methods
Eighty patients with UC were randomly assigned to consume either 1 g/day (two 500 mg capsules/day) of SP (n = 40) or control (n = 40) for 8 weeks. Dietary intakes, physical activity, disease activity, health-related quality of life, antioxidant status, erythrocyte sedimentation rate (ESR), and serum PTX-3 levels were assessed and compared between groups at baseline and post-intervention.
Results
Seventy-three patients (91.3%) completed the trial. We observed increases in serum total antioxidant capacity levels in the SP supplementation group compared to the control group after 8 weeks of intervention (p ≤ 0.001). A within-group comparison indicated a trend towards a higher health-related quality of life score after 8 weeks of taking two different supplements, SP (p < 0.001) and PL (p = 0.012), respectively. However, there were no significant changes in participant’s disease activity score in response to SP administration (p > 0.05). Similarly, changes in ESR and PTX-3 levels were comparable between groups post-intervention (p > 0.05).
Conclusions
SP improved antioxidant capacity status and health-related quality of life in patients with UC. Our findings suggest that SP supplementation may be effective as an adjuvant treatment for managing patients with UC. Larger trials with longer interventions periods are required to confirm our findings.
... In contrast, under conditions of chronic inflammation, like IBDs, leptin release is inhibited [22]. In fact, most studies showed that the circulating leptin levels were found to be decreased in patients with IBDs compared with healthy controls [13,18,35]. The decreased serum leptin levels of patients with IBD could be partially attributed to an elevated circulating TNF-α, which has already been shown to inhibit the expression, synthesis, and release of leptin in vitro [30,31]. ...
... Furthermore, serum resistin levels have been found to be elevated in inflammation-related diseases such as type 2 diabetes mellitus, coronary atherosclerosis, chronic kidney disease, rheumatoid arthritis, and/or sepsis [41]. In IBD patients, serum resistin levels were found to be elevated, and in the creeping fat from CD patients, resistin mRNA is overexpressed, suggesting that this pro-inflammatory adipokine may play an important role in the pathophysiology of IBDs (especially in CD) [35]. Interestingly, TNF-α, but not other pro-inflammatory cytokines such as IL-6 and IL-1β, induced resistin mRNA expression, suggesting that this adipokine is markedly elevated in IBD patients as a response to the sustained increase in TNF-α levels in these patients [32]. ...
Introduction: Inflammatory bowel diseases (IBDs) are idiopathic inflammations of the colon, which can often undergo remission with the use of specific anti-TNF antibodies such as the infliximab. Although that the therapeutic monitoring can provide valuable insight into the possible etiolog y of unfavorable outcomes and allow for an appropriate management strateg y for these patients, currently none technique or biomarker have proved ideal for the evaluation of therapeutic benefices of anti-TNF antibodies in IBDs. Aim: To summarise current knowledge on the role of serum adipokines as potential biomarkers for the therapeutic monitoring of patients with IBDs under infliximab. Methods: A systematic review was carried out in the PubMed/MEDLINE, Cochrane Library, Scopus and Biblioteca Virtual em Saúde databases. Next, the meta-analysis was performed with the mean values of serum adipokine levels in patients with IBDs before and after the use of infliximab using the Review Manager (RevMan) ® 5.3 software. Results: Three studies that together included 58 patients diagnosed with IBDs and treated with infliximab at 5 mg/kg were selected. According to the quantitative analysis, serum leptin levels were significantly increased after the use of infliximab (p-value=0.01; Heterogeneity: I2=61%), which is correlated with the clinical remission of the disease. In addition, the circulating adiponectin (p-value=0.006; Heterogeneity: I2=0%) and resistin (p-value=0.009; Heterogeneity: I2=93%) concentrations were both reduced after the clinical remission of IBD with the use of infliximab. Conclusion: Serum leptin levels are significantly increased, while circulating adiponectin and resistin is reduced among IBD patients after the use of infliximab.
... The ghrelin system demonstrates mainly anti-inflammatory properties, through the regulation of both anti-inflammatory (e.g., IL-10, IL-4, transforming growth factor β (TGF-β) (stimulation)), and proinflammatory cytokines (e.g., TNF-α, interferon gamma (IFN-γ), IL-1β, IL-6 (inhibition)). It can also play a role in the pathogenesis of human IBD [31,33,112,120,121], including UC, CD, and microscopic colitis [51]. Active intestinal inflammatory process increases endogenous ghrelin production [120]. ...
... It can also play a role in the pathogenesis of human IBD [31,33,112,120,121], including UC, CD, and microscopic colitis [51]. Active intestinal inflammatory process increases endogenous ghrelin production [120]. The IBDs also penetrate the visceral adipose tissue (AT), which may be an additional source of cytokines and adipokines (including ghrelin) responsible for the inflammatory process in these diseases (reviewed in: [33]). ...
It is not known exactly what leads to the development of colorectal cancer (CRC) and hepatocellular carcinoma (HCC), but there are specific risk factors that increase the probability of their occurrence. The unclear pathogenesis, too-late diagnosis, poor prognosis as a result of high recurrence and metastasis rates, and repeatedly ineffective therapy of both cancers continue to challenge both basic science and practical medicine. The ghrelin system, which is comprised of ghrelin and alternative peptides (e.g., obestatin), growth hormone secretagogue receptors (GHS-Rs), and ghrelin-O-acyl-transferase (GOAT), plays an important role in the physiology and pathology of the gastrointestinal (GI) tract. It promotes various physiological effects, including energy metabolism and amelioration of inflammation. The ghrelin system plays a role in the pathogenesis of inflammatory bowel diseases (IBDs), which are well known risk factors for the development of CRC, as well as inflammatory liver diseases which can trigger the development of HCC. Colitis-associated cancer serves as a prototype of inflammation-associated cancers. Little is known about the role of the ghrelin system in the mechanisms of transformation of chronic inflammation to low- and high-grade dysplasia, and, finally, to CRC. HCC is also associated with chronic inflammation and fibrosis arising from different etiologies, including alcoholic and nonalcoholic fatty liver diseases (NAFLD), and/or hepatitis B (HBV) and hepatitis C virus (HCV) infections. However, the exact role of ghrelin in the progression of the chronic inflammatory lesions into HCC is still unknown. The aim of this review is to summarize findings on the role of the ghrelin system in inflammatory bowel and liver diseases in order to better understand the impact of this system on the development of inflammatory-related cancers, namely CRC and HCC.
... Anorexia is another feature present in CD which could be explained by cytokine overproduction by mWAT [126]. It is generally accepted that reduced food intake may occur in CD and can lead to abdominal pain, fear of diarrhoea and incontinence, surgery, nausea, and depression. ...
... It is generally accepted that reduced food intake may occur in CD and can lead to abdominal pain, fear of diarrhoea and incontinence, surgery, nausea, and depression. Satiety control in these patients could be modulated by inflammatory cytokines, which generally may suppress appetite [126]. ...
Inflammatory bowel diseases (IBDs) are a group of disorders which include ulcerative colitis and Crohn’s disease. Obesity is becoming increasingly more common among patients with inflammatory bowel disease and plays a role in the development and course of the disease. This is especially true in the case of Crohn’s disease. The recent results indicate a special role of visceral adipose tissue and particularly mesenteric adipose tissue, also known as “creeping fat”, in pathomechanism, leading to intestinal inflammation. The involvement of altered adipocyte function and the deregulated production of adipokines, such as leptin and adiponectin, has been suggested in pathogenesis of IBD. In this review, we discuss the epidemiology and pathophysiology of obesity in IBD, the influence of a Western diet on the course of Crohn’s disease and colitis in IBD patients and animal’s models, and the potential role of adipokines in these disorders. Since altered body composition, decrease of skeletal muscle mass, and development of pathologically changed mesenteric white adipose tissue are well-known features of IBD and especially of Crohn’s disease, we discuss the possible crosstalk between adipokines and myokines released from skeletal muscle during exercise with moderate or forced intensity. The emerging role of microbiota and the antioxidative and anti-inflammatory enzymes such as intestinal alkaline phosphatase is also discussed, in order to open new avenues for the therapy against intestinal perturbations associated with IBD.
... Adipose tissue is an active endocrine organ that is made up of elements of connective tissue as well as of cells represented by pre-adipocytes and adipocytes that may be prominent mediators of inflammation in the human body [6][7][8][9].Abnormally increased stores of adipose tissue in the body represent obesity which is measured as increased body weight to height ratio, also referred to as the body mass index (BMI). Standard weight is defined as BMI of 18.5 -24.9 kg/m 2 . ...
... The importance of the need to study the association between the obese state and CD outcomes emanates from the observation that there is credible molecular evidence for a link between increased mesenteric adipose stores and intestinal inflammation in CD [8,9]. Moreover, in the past few Manuscript accepted for publication June 20, 2013 a decades, obesity has undergone a marked increase in prevalence within the US and across the globe, and this increased trend of obesity is also reflected in patients with CD [10][11][12]. ...
Background
Published data suggest a link between obesity and adverse outcomes in Crohn’s disease (CD). We aimed to test the hypothesis that obese CD patients would be more likely than non-obese CD patients to have poor surgical outcome when undergoing surgery for a complication of CD.
Methods
We designed a retrospective cohort study to test our hypothesis. The population comprised of adult CD patients who underwent CD related surgery at a tertiary referral center. The exposed and unexposed cohorts were represented by patients who were obese vs. non-obese at the pre-op visit respectively. Outcome was represented by successful vs. unsuccessful surgical outcome as deemed by the treating clinician.
Results
Ninety CD patients were eligible for inclusion into this cohort study of which 36 were obese (exposed cohort) and 54 were non-obese (unexposed cohort). Among obese CD patients, 64% had an unsuccessful surgical outcome vs. 41% with unsuccessful surgical outcome among the non-obese. Based on unadjusted bivariate analysis, potential confounders identified included age and type of surgery. Gender distribution, disease duration, ethnicity, tobacco use, steroid use, traditional and biological immune modulator use and clinical disease activity were similar between the two groups. Logistic regression adjusted for age and type of surgery revealed that obese CD patients were approximately 2.5 times more likely to have a poor surgical outcome than patients with CD who were not obese (P = 0.05 OR 2.53 95% CI 0.99 - 6.52). BMI as a continuous variable (adjusted for age and type of surgery) appeared to be associated with poor surgical outcome (P = 0.06 OR 1.07 95% CI 0.99 - 1.15).
Conclusions
Obesity may be associated with poor surgical outcome in CD patients.
... In acute flares period during colitis, resting energy expenditure was shown to increase and high proinflammatory cytokines levels related to this state, exert an anorexic effect [34]. This inflammatory state was shown to alter the levels of certain metabolic hormones controlling satiety, among which are adiponectin, leptin, and ghrelin [35]. Also, IBD patients are characterized by an enhanced gastrocolic reflex and pain often associated with ingestion of food, which usually leads to avoidance of food by these patients [34]. ...
... It promotes the survival of nave T cells and the production of tumor necrosis factor α (TNF-α) and IL-12 and facilitates Th1 cell differentiation and activity while inhibiting Th2 cells (3). Serum leptin levels are associated with a variety of infectious and immune-mediated diseases, such as systemic lupus erythematosus (4), rheumatoid arthritis (5), multiple sclerosis (6), and CD (7). Independent studies have revealed a strong upregulation of leptin expression in the mesenteric fat of CD patients. ...
Background: Leptin is thought to play an important role in Crohn's disease (CD) pathogenesis and progression. Independent studies have revealed a strong upregulation of leptin expression in the mesenteric fat of CD patients. Objectives: This study assessed the relationship between leptin gene polymorphisms and CD susceptibility in a Chinese pediatric population. Methods: A total of 86 patients with CD and 142 healthy controls were recruited for this case-control study. The genotypes of 4 single-nucleotide polymorphisms (SNPs; rs2071045, rs41457646, rs11761556, and rs2167270) in the leptin gene were determined by multiplex polymerase chain reaction (PCR) combined with next-generation sequencing. Results: We found that leptin rs2167270 had a significantly different distribution of alleles and genotypes between CD patients and healthy controls (G is a risk allele: 83.7% of cases vs 72.5% of controls; odds ratio [OR] 1.947; 95% CI, 1.203-3.151; P = 0.006; GG is a risk genotype: 72.1% of cases vs 53.5% of controls; P = 0.021). Patients with the CC genotype (rs2071045) had a significantly increased risk of early onset of CD (58.3% in A1a vs 31.1% in A1b; P = 0.003). Similarly, patients carrying the G allele (100% in A1a vs 84.1% in A1b; P = 0.015) and GG genotype (100% in A1a vs 71.0% in A1b; P = 0.048) of rs41457646, A allele (93.3% in A1a vs 71.8% in A1b; P = 0.013) and AA genotype (93.3% in A1a vs 47.9% in A1b; P = 0.003) in rs11761556 had a higher risk of early onset of CD. However, there was no significant difference in any of these 4 SNPs between patients with and without perianal lesions, as well as in low and normal body mass index (BMI) patients. Conclusions: The leptin rs2167270 polymorphism is associated with the susceptibility to CD in a Chinese pediatric population. Leptin rs2071045, rs41457646, and rs11761556 might lead to the early onset of pediatric CD.
... 104 Some researchers confirm that the upregulation of ghrelin is an attempt to counter tissue damage following intestinal inflammation; damage may stimulate the secretion of endogenous ghrelin. 105 Coincidentally, a prospective clinical study in China demonstrated that serum ghrelin was negatively associated with esophageal and gastric cancer, implying the potential role of ghrelin as a marker of gastric mucosal alterations in upper gastrointestinal cancers. 106,107 Thus, further understanding of ghrelin's role in gastrointestinal inflammation is warranted. ...
Several diseases are caused or progress due to inflammation. In the past few years, accumulating evidence suggests that ghrelin, a gastric hormone of 28‐amino acid residue length, exerts protective effects against inflammation by modulating the related pathways. This review focuses on ghrelin's anti‐inflammatory and potential therapeutic effects in neurological, cardiovascular, respiratory, hepatic, gastrointestinal, and kidney disorders. Ghrelin significantly alleviates excessive inflammation and reduces damage to different target organs mainly by reducing the secretion of inflammatory cytokines, including interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), and tumor necrosis factor‐α (TNF‐α), and inhibiting the nuclear factor kappa‐B (NF‐κB) and NLRP3 inflammasome signaling pathways. Ghrelin also regulates inflammation and apoptosis through the p38 MAPK/c‐Jun N‐terminal kinase (JNK) signaling pathway; restores cerebral microvascular integrity, and attenuates vascular leakage. Ghrelin activates the phosphoInositide‐3 kinase (PI3K)/protein kinase B (Akt) pathway and inhibits inflammatory responses in cardiovascular diseases and acute kidney injury. Some studies show that ghrelin exacerbates colonic and intestinal manifestations of colitis. Interestingly, some inflammatory states, such as non‐alcoholic steatohepatitis, inflammatory bowel diseases, and chronic kidney disease, are often associated with high ghrelin levels. Thus, ghrelin may be a potential new therapeutic target for inflammation‐related diseases.
... After that, resisting could also be related to malignancies associated with obesity by triggering the nuclear factor-B (NF-B) pathway and amplifying the procardiogenic actions of interleukin (IL)-1, IL-6 and TNF-ἀ, respectively. To present, in breast cancer, non-small cell lung cancer and in digestive tumors, a presumed role of resisting has been reported (94)(95)(96). IR-associated low-grade chronic inflammation also promotes the activation of macrophages and the large secretion into the systemic circulation of many proinflammatory cytokines, such as IL-6 and TNFἀ. Animal models have shown a correlation between TNF ἀ and various malignancies, like CCR (97)(98)(99). ...
... Accumulating studies showed a link between altered mesenteric fat (aka creeping fat) and IBD, mainly in CD [182,183]. Low-grade inflammation, on the other hand, can cause an imbalance between leptin/adiponectin ratio and increase intestinal permeability, bacterial translocation, and T-cell infiltration, thus, predisposing an obese individual to IBD [184], as depicted in Figure 7. Karmiris et al. showed that downregulation of leptin expression in mesenteric fat may be due to the inflammatory milieu in IBD patients due to increased production of TNF-α [185]. However, other conflicting studies have shown that leptin levels increased or remained unchanged in IBD [186,187]. ...
The gut microbiota is a complex community of microorganisms that has become a new focus of attention due to its association with numerous human diseases. Research over the last few decades has shown that the gut microbiota plays a considerable role in regulating intestinal homeostasis, and disruption to the microbial community has been linked to chronic disease conditions such as inflammatory bowel disease (IBD), colorectal cancer (CRC), and obesity. Obesity has become a global pandemic, and its prevalence is increasing worldwide mostly in Western countries due to a sedentary lifestyle and consumption of high-fat/high-sugar diets. Obesity-mediated gut microbiota alterations have been associated with the development of IBD and IBD-induced CRC. This review highlights how obesity-associated dysbiosis can lead to the pathogenesis of IBD and CRC with a special focus on mechanisms of altered absorption of short-chain fatty acids (SCFAs)
... Dysbiosis and altered gut signaling induced by IBD, acting through hormones, satietyrelated peptides, and bile acids, could be responsible for the onset of obesity and dysmetabolism. Smoking cessation and the use of corticosteroids in this setting can also contribute to weight gain [27,28]. Just as in the non-IBD population, the establishment of NAFLD is conventionally explained by the "multiple hit" hypothesis, which considers multiple insults acting together on genetically predisposed subjects. ...
Steatohepatitis and hepatobiliary manifestations constitute some of the most common extra-intestinal manifestations of Inflammatory Bowel Disease (IBD). On the other hand, non-alcoholic fatty liver disease (NAFLD) affects around 25% of the world’s population and is attracting ever more attention in liver transplant programs. To outline the specific pathways linking these two conditions is a pressing task for 21st-century researchers. We are accustomed to expecting the occurrence of fatty liver disease in obese people, but current evidence suggests that there are several different pathways also occurring in underweight patients. Genetic factors, inflammatory signals and microbiota are key players that could help in understanding the entire pathogenesis of NAFLD, with the aim of defining the multiple expressions of malnutrition. In the current review, we summarize the most recent literature regarding the epidemiology, pathogenesis and future directions for the management of NAFLD in patients affected by IBD.
... Patients with chronic periodontitis have significantly higher concentrations of ghrelin in the peripheral blood serum, as compared to the control group [55]. High concentrations of ghrelin are also found in many chronic inflammatory conditions, such as Leśniowski-Crohn disease and inflammatory bowel disease [56]. ...
Eating food is one of the most complicated behaviours in mammals, especially humans. The primary function of ghrelin is regulation of the appetite level and its stimulation. It is also responsible for the body's energy balance and glucose homeostasis. Ghrelin has been shown to affect many brain structures, which confirms the presence of ghrelin receptors in the brain. Studies are also conducted to assess the possible role of ghrelin in anxiety states and in memory disorders and motor dysfunctions. Ghrelin has been found in saliva and salivary glands, teeth and gums, and in the taste buds of the tongue epithelium; it is also secreted by mucosal cells and gingival fibroblasts. The presence of ghrelin in developmental enamel, especially in odontoblasts and ameloblasts, may suggest its regulatory role in the development of teeth. Patients with chronic periodontitis have significantly higher concentrations of ghrelin in the peripheral blood serum, as compared to the control group. Ghrelin plays a special role in the proliferation of cancer cells and in the development of neoplastic metastases. The abundant presence of ghrelin receptors in cancer cells is considered an important target in the treatment of neoplasms. Ghrelin is a hormone whose multidirectional mechanism of action has not yet been fully understood. However, its ubiquitous occurrence in the human body and its very diverse participation in metabolic processes may prove to be a significant obstacle in achieving the expected clinical effect of ghrelin as an effective drug in selected disease units.
... Among these, leptin, resistin, adiponectin, and secreted frizzled-related protein 5 (SRFP5) may play promising key roles in the development and suppression of the inflammatory response, and their role has been confirmed in other inflammatory disorders, such as CD. 39 Abnormal adipokine secretion appears to be involved in the pathogenesis of different inflammatory diseases. Fat wrapping or "creeping fat", defined as WAT hypertrophy and extension, is positively correlated with increased inflammatory processes, and macrophage and lymphocyte perivascular infiltration. ...
Cryptoglandular perianal fistula is a common benign anorectal disorder that is managed mainly with surgery. A fistula is typically defined as a pathological communication between two epithe-lialized surfaces. More specifically, perianal fistula manifests as an abnormal tract between the anorectal canal and the perianal skin. Perianal fistulas are often characterized by significantly decreased patient quality of life. The cryptoglandular theory of perianal fistulas suggests their development from the proctodeal glands, which originate from the intersphincteric plane and perforate the internal sphincter with their ducts. Involvement of proctodeal glands in the inflam-matory process could play a primary role in the formation of cryptoglandular perianal fistula. The objective of this narrative review was to investigate the current knowledge of the pathogenesis of cryptoglandular perianal fistula with the specific aims of characterizing the potential role of proinflammatory factors responsible for the development of chronic inflammation. Further studies are crucial to improve the therapeutic management of cryptoglandular perianal fistulas.
... Some studies even link these sex differences to changes in the microbiome, making this even more relevant to IBD [40]. Finally, adipokines, such as leptin, adiponectin, resistin, and possibly ghrelin, which are increased in CD likely through inflammation, possibly also have relevant roles as they impact appetite and other growth-related hormonal pathways and are also linked to adipose tissue changes and creeping fat [41]. ...
Growth delay with height and weight impairment is a common feature of pediatric inflammatory bowel diseases (PIBD). Up to 2/3 of Crohn Disease patients have impaired weight at diagnosis, and up to 1/3 have impaired height. Ulcerative colitis usually manifests earlier with less impaired growth, though patients can be affected. Ultimately, growth delay, if not corrected, can reduce final adult height. Weight loss, reduced bone mass, and pubertal delay are also concerns associated with growth delay in newly diagnosed PIBD patients. The mechanisms for growth delay in IBD are multifactorial and include reduced nutrient intake, poor absorption, increased fecal losses, as well as direct effects from inflammation and treatment modalities. Management of growth delay requires optimal disease control. Exclusive enteral nutrition (EEN), biologic therapy, and corticosteroids are the primary induction strategies used in PIBD, and both EEN and biologics positively impact growth and bone development. Beyond adequate disease control, growth delay and pubertal delay require a multidisciplinary approach, dependent on diligent monitoring and identification, nutritional rehabilitation, and involvement of endocrinology and psychiatry services as needed. Pitfalls that clinicians may encounter when managing growth delay include refeeding syndrome, obesity (even in the setting of malnutrition), and restrictive diets. Although treatment of PIBD has improved substantially in the last several decades with the era of biologic therapies and EEN, there is still much to be learned about growth delay in PIBD in order to improve outcomes.
... More and more researchers draw attention to the link between leptin and IBD. Karmiris et al., indicate that leptin messenger RNA (mRNA) may be overexpressed in the mesenteric WAT, which results in the enhancement of mesenteric TNF-α, thereby enhancing the inflammatory process in the body of IBD patients [48]. Zhao et al., demonstrate the beneficial effects of adiponectin in improving the integrity of intestinal mucosa and alleviating the symptoms of dextran sulfate sodium (DSS) inflammation in Caco-2 cells [49]. ...
A sedentary lifestyle and inadequate nutrition often leads to disturbances in intestinal homeostasis, which may predispose people to excess body weight and metabolic syndrome. Obesity is frequently observed in patients with inflammatory bowel diseases (IBD), similar to the general population. Obesity may exert a negative effect on the course of IBD as well as reduce the response to treatment. Moreover, it may also be an additional risk factor for vein thromboembolism during the flare. In both obesity and IBD, it is of great importance to implement proper dietary ingredients that exert desirable effect on gut microbiota. The key to reducing body mass index (BMI) and alleviating the course of IBD is preserving healthy intestinal microflora.
... Leptin is an adipokine secreted by adipocytes which stimulates the production of pro-inflammatory IL-1β and IL-6 in T cells 11 . Adiponectin is secreted from adipocytes and displays anti-inflammatory properties 12 . ...
Abstract Adipose tissue secretes molecules that can promote activity in Crohn’s disease. We aimed to evaluate the role of serum adipokines as possible biomarkers in Crohn’s disease. Serum samples were obtained from 40 patients with endoscopically active or quiescent Crohn’s disease and 36 healthy controls. Serum leptin, ghrelin, resistin and adiponectin levels were analysed by Multiplex in a Luminex 200 system technology. Receiver Operating Characteristic curves were performed to evaluate the adipokines discriminatory capacity. A logistic regression adjusted by possible confounders (i.e. gender, age, BMI) was performed for those adipokines that showed an area under the curve > 0.7. No differences were found in age, gender or BMI among groups. Distribution for serum resistin was different among the three groups of study, and only this adipokine showed an area under the curve of 0.75 comparing actives patients and healthy control groups. Resistin median concentration was selected as a cut-off for a logistic regression analysis; odds ratio along its 95% confidence interval adjusted by gender, age, and BMI yielded a value of 5.46 (1.34–22.14) comparing actives patients and healthy controls. High concentration of serum resistin is probably associated to activity, being this association independent of gender, age or BMI.
... .) mais dans tous les cas l'adiponectine semble participer au maintien de l'homéostasie intestinale. L'effet anti-ou proinflammatoire pourrait varier selon les cellules cibles et leur microenvironnement inflammatoire [46]. L'adiponectine accroît la prolifération de l'épithélium intestinal et protège ses cellules de l'apoptose, augmentant ainsi l'effet de barrière. ...
Adiponectin is a major adipokine involved in energy homeostasis that exerts insulin-sensitizing properties. The level of adiponectin is reduced in situations of insulin resistance and is negatively associated with several pathophysiological situations including abdominal obesity, metabolic syndrome, steatosis and non-alcoholic steatohepatitis, type 2 diabetes, some cancers and cognitive diseases. These aspects are discussed in this review.
... La leptine, par son effet modulateur de diverses réponses immunitaires (activation des cellules T vers une réponse Th1, et NK) pourrait être d'une part impliquée dans le caractère auto-immun de la maladie de Crohn. D'autre part, son effet favorisant la sécrétion de cytokines proinflammatoires, et la surexpression de son ARNm dans le tissu adipeux mésentérique en comparaison à des sujets témoins [49], pourraient expliquer en partie la réponse inflammatoire observée dans la rectocolite hémorragique (RCH) et dans la maladie de Crohn, et plus hypothétiquement l'anorexie et l'amaigrissement des patients [50]. Par ailleurs, dans la colite ulcérative, les cellules épithéliales inflammatoires du côlon produisent de la leptine dans la lumière intestinale, ce qui en retour entraîne l'érosion de l'épithélium et son infiltration par les neutrophiles. ...
The identification of leptin allowed the discovery of a new endocrine system. This major adipokine controlling energy homeostasis is also involved in the regulation of neuroendocrine function and fertility. Unfortunately, leptin is not able to treat common obesity, which associates hyperleptinemia and resistance to the hormone. Conversely, treatment with recombinant leptin is effective in situations of leptin deficiency. Several pathophysiological situations associated with adipose tissue dysfunctions and abnormal regulation of leptin secretion are discussed in this review. The advantage of the potential use of the leptin assay in some pathophysiological conditions is proposed.
... It is well known that active muscles release several cytokines and other peptides, and exert anti-inflammatory action, which in turn decrease ROS production. Several studies investigated changes in adiponectin, leptin and ghrelin following exhaustive acute and chronic exercise training, related with inflammatory markers [115]. All these studies reported a significant increase in plasma levels of ghrelin and adiponectin and a decrease in leptin in absence of weight loss. ...
The evidence about the health benefits of regular physical activity is well established. Exercise intensity is a significant variable and structured high-intensity interval training (HIIT) has been demonstrated to improve both whole-body and skeletal muscle metabolic health in different populations. Conversely, fatigue accumulation, if not resolved, leads to overwork, chronic fatigue syndrome (CFS), overtraining syndrome up to alterations of endocrine function, immune, systemic inflammation, and organic diseases with health threat. In response to temporary increases in stress during training, some athletes are unable to maintain sufficient caloric intake, thus suffering a negative energy balance that causes further stress. The regulation of the energy balance is controlled by the central nervous system through an elaborate interaction of the signaling that involves different tissues such as leptin, adiponectin and ghrelin whose provide important feedback to the hypothalamus to regulate the energy balance. Although exercise-induced reactive oxygen species are required for normal force production in muscle, high levels of ROS appear to promote contractile dysfunction. However, a high level of oxidative stress in may induce a rise in inflammatory markers and a disregulation in expression of adiponectin, leptin and grelin.
... We also noted negative correlation between WC as well as TG and LDL-C levels, on one hand, and the markers of local inflammation, mRNA levels of IL23A, IL17F, IL17A, and TLR9 in inflamed colon of UC patients, on the other hand (although not significant after FDR correction). Interestingly, although central obesity contributes to IBD pathogenesis, 10 increased intestinal inflammation, in turn, might cause reduction in central obesity of IBD patients as noted in this and other studies, 44 probably attributed to nutrition malabsorption. Therefore, although our results showed that patients on diagnosis were more obese than controls, they could still have different levels of malnutrition among themselves, depending on the level of intestinal damage, which is related to the level of local inflammation. ...
Background:
This study analyzed poorly understood relationship of two overlapping conditions: metabolic syndrome (MeS) and inflammatory bowel disease (IBD), both associated with inflammation in the visceral adipose tissue.
Methods:
Newly diagnosed 104 IBD patients, of which 50 Crohn's disease (CD) and 54 ulcerative colitis (UC), and 45 non-IBD controls were examined for MeS-related obesity and lipid markers. Th-17 immune genes IL17A, IL17F, IL23A, and TLR9 mRNAs were measured in intestinal mucosa by qRT-PCR. Subjects were genotyped for obesity-associated FTO variant rs9939609 by polymerase chain reaction-amplification refractory mutation system.
Results:
CD was associated with MeS (P = 0.01), while both CD and UC were associated with central obesity (P = 10-5, P = 0.002, respectively) and low levels of high-density lipoprotein (HDL) cholesterol (P = 5 × 10-6, P = 6 × 10-6, respectively). IBD lipid profile was characterized by decreased total and HDL cholesterol, while low-density lipoprotein cholesterol was reduced only in CD. Negative correlations were found between total cholesterol and CD activity index (P = 0.005), waist circumference and IL17A as well as IL17F mRNA levels in inflamed CD colon (P = 0.003, P = 0.001, respectively). Carriers of FTO rs9939609 AA genotype showed increased risk of CD (OR 2.6, P = 0.01).
Conclusions:
MeS, central obesity, and dyslipidemia could be important for IBD pathogenesis. This could influence therapeutic approaches and prevention strategies in high-risk groups.
... On the contrary, Chen et al. [31] observed an increased plasma of homocysteine. Moreover, it was suggested that adipocytes may play a crucial role by actively participating in systemic immune responses in IBD patients, where leptin and adiponectin are associated with the disease severity and, similarly in our study, may show significant alterations of circulating serum levels of these adipokines in IBD patients [32,33]. For future monitoring of IBD activity, 78% of gastroenterologists from Switzerland considered clinical activity to be a more relevant criterion, whereas 15% preferred endoscopic severity and 7% preferred biomarkers [34]. ...
The aim of the study was to show the clinical magnitude of short-term feeding: enteral nutrition (EN) combined with parenteral nutrition (PN) in active Crohn’s disease and ulcerative colitis patients. Among 122 eligible inflammatory bowel disease (IBD) patients, 65 met the inclusion criteria. Combined EN and PN was administered for 21 days, wherein over the first 3–5 days of treatment, trophic enteral nutrition (300 kcal/day) was used with an energy increase of up to 1500 kcal. An EN was administered using a nasogastric tube or, in case of intolerance, using a naso-jejunal tube. For PN, the “All in One” system was used according to individually prepared admixtures (ESPEN Guidelines). In addition to routine blood measurement (i.e., ALAT, ASPAT, GGTP, creatinine, lipid profile), the following parameters were assessed: adiponectin, leptin, (hs)TNF-α, hsIL-6 and hsIL-10, TSH, NT-proBNP, serum vitamin B12 concentration, and tHcy. The results showed a considerable improvement in all clinically significant parameters (p < 0.05), showing the benefits and importance of short-term well-balanced EN combined with PN for nutritional and clinical status in IBD patients with active disease. The daily work at hospitals with active IBD patients demonstrates the potential of continued administration of home-based nutrition by patients.
... Weight loss is an indicator of the severity of intestinal inflammation and correlates with the histopathological changes of colitis 19 . Weight loss could be contributed to the inflammatory state in IBD which results in mal-absorption of nutrients; a generalized catabolic state; and alterations in the levels of metabolic hormones affecting satiety 20,21 . ...
Ulcerative colitis (UC) is among the most challenging human diseases. Nanotechnology has incontestable promising outcomes in inflammatory bowel diseases. This study aimed to investigate the therapeutic effect of naked gold nanoparticles (AuNPs) on dextran sodium sulphate (DSS) induced ulcerative colitis in mice. We also examined the expression of interleukin-17 (IL-17) following AuNPs treatment. Mice were randomly divided into control, DSS and DSS+ AuNPs groups. Severity of colitis was assessed by disease activity index (DAI) measurement. At the end of the experiment, the final body weights were recorded. The colon was dissected and processed for histopathological examinations by light and electron microscopes. Colon homogenates were prepared for assay of tissue malondialdehyde (MDA) and real-time PCR analysis of IL-17A. Immunohistochemical localization of IL-17A was carried out. Scanning electron microscopy (SEM) and Energy Dispersive X-ray (EDX) detector were used to detect the presence of AuNPs in the colonic tissue of DSS+ AuNPs groups. Our results showed that AuNPs effectively targeted the colonic tissue, and reduced changes induced by DSS. The underlying mechanisms could be related to anti-oxidant effect (as evident by decreasing tissue MDA) and anti-inflammatory potential of AuNPs. Our study draws attention to as a novel therapeutic strategy for treating UC.
... Functions in adaptive immunity include thymic homeostasis, naïve CD4 + cell proliferation, promotion of T helper 1 (T H 1) responses and suppression of CD4 + CD25 high regulatory T cells (Tregs) [18]. Consequently, leptin can contribute to the onset and progression of several T cell-controlled autoimmune diseases, including Crohn's disease [19,20], rheumatoid arthritis [21,22], multiple sclerosis [23,24] and autoimmune hepatitis [25][26][27]. Furthermore, clinical reports unequivocally link elevated serum leptin levels (caused by obesity) to an increased risk of certain cancers including prostate [28], breast [29,30], colorectal [31], renal cancers [32] and multiple myeloma [33,34]. ...
Leptin links body energy stores to high energy demanding processes like reproduction and immunity. Based on leptin’s role in autoimmune diseases and cancer, several leptin and leptin receptor (LR) antagonists have been developed, but these intrinsically lead to unwanted weight gain. Here, we report on the uncoupling of leptin’s metabolic and immune functions based on the cross talk with the epidermal growth factor receptor (EGFR). We show that both receptors spontaneously interact and, remarkably, that this complex can partially overrule the lack of LR activation by a leptin antagonistic mutein. Moreover, this leptin mutant induces EGFR phosphorylation comparable to wild-type leptin. Exploiting this non-canonical leptin signalling pathway, we identified a camelid single-domain antibody that selectively inhibits this LR-EGFR cross talk without interfering with homotypic LR signalling. Administration in vivo showed that this single-domain antibody did not interfere with leptin’s metabolic functions, but could reverse the leptin-driven protection against starvation-induced thymic and splenic atrophy. These findings offer new opportunities for the design and clinical application of selective leptin and LR antagonists that avoid unwanted metabolic side effects.
... Alteration in body fat distribution, with accumulation of intraabdominal white adipose tissue (WAT) is a well-known feature of CD. Mesenteric WAT (mWAT) or creeping fat (CF) is mainly hypertrophied around the intestine involved with inflammatory infiltration [7]. Recent studies suggest that WAT, besides its wellestablished functions, also produces and releases a great number of multifunctional proteins and those released exclusively by WAT are collectively named adipokines. ...
Crohn’s disease (CD) is a chronic, immune system-mediated inflammatory disease affecting gastrointestinal (GI) tract. The pathogenesis of the intestinal lesions is not entirely explained and understood: excessive activation of the immune system may come as a result of the interaction of environmental, genetic and infectious factors and the mediation of abnormal intestinal flora. The main objective of the current study is to further identify the role of adipose tissue in the pathogenesis of CD. Alterations in body fat distribution, accumulation of intra-abdominal white adipose tissue (WAT) and mesenteric obesity are well-known features of CD. Up to date, data concerning the role of WAT in the pathogenesis of CD is limited with only a few studies on the relationship between WAT and the course of the disease, as well as pro- and anti-inflammatory cytokine profile and general immune system functioning.
In this review, we focus on the importance of physiological and pathophysiological WAT functions and secreted adipokines, which seem to have a vital role in the inflammatory and fibrotic processes in CD sufferers.
... Leptin is considered a multi-task hormone 57-62 as well as an important regulator of inflammation 37 (Table 1) Leptin has important modulatory effects on the immune system. Leptin modifies the cytokine production pattern toward a type 1 T-cell helper response by promoting the release of interleukin IL-2 and interferon and inhibiting IL-4 secretion, reverses starvation-induced immunosuppression 37,10 , and directly stimulates the expression and release of IL-1 and tumor necrosis factor-α by T cells 38 . ...
... 35 Adiponectin may play both anti-and pro-inflammatory roles and is increased in the mesenteric adipose tissue of CD patients. 36,37 In contrast, leptin antagonists are being studied as possible therapeutics in IBD. 38 There are several strengths and limitations to this study. ...
Background:
Case series suggest a possible association between bariatric surgery and incident IBD.
Aim:
The aim of this study was to evaluate the association between bariatric surgery and new-onset IBD.
Methods:
We first conducted a multi-institutional case series of patients with a history of IBD and bariatric surgery. We next conducted a matched case-control study using medical and pharmacy claims from 2008 to 2012 in a US national database from Source Healthcare Analytics LLC. Bariatric surgery was defined by ICD-9 or CPT code. Bariatric surgery was evaluated as recent (code in database timeframe), past (past history V code) or no history. Conditional logistic regression was used to estimate odds ratios (OR) and 95% CI for new-onset IBD, CD and UC.
Results:
A total of 15 cases of IBD (10 CD, 4 UC, 1 IBD, type unclassified) with a prior history of bariatric surgery were identified. Most cases were women, had Roux-en-Y surgery years prior to diagnosis and few IBD-related complications. A total of 8980 cases and 43 059 controls were included in our database analysis. Adjusting for confounders, a past history of bariatric surgery was associated with an increased risk of new-onset IBD (OR 1.93, 95% CI 1.34-2.79). However, patients who had recent bariatric surgery did not appear to be at shorter term risk of IBD (OR 0.94, 95% CI 0.58-1.52).
Conclusion:
New-onset IBD was significantly associated with a past history of bariatric surgery. This potential association needs to be confirmed in future prospective studies.
... Many factors related to CD pathogenesis have been proposed as playing a role in this weight loss, including the anorectic and catabolic effects of pro-inflammatory cytokines [28], alteration in production of the adipokines leptin and adiponectin [29], dietary restriction to alleviate symptoms [30], and micro-nutrient deficiencies [31]. Why these issues are more prominent in some forms of CD and younger rather older onset is unclear. ...
Background
Crohn’s disease (CD) has traditionally been associated with weight loss and low BMI, yet paradoxically obesity has recently been suggested as a risk factor for CD, but not for ulcerative colitis (UC). We therefore hypothesized that the relation between BMI and CD is U shaped.
Aim
To conduct a large population-based prospective cohort study of BMI and later risk of IBD, taking age at IBD diagnosis into account.
Methods
A cohort of 74,512 women from the Danish National Birth Cohort, with BMI measured pre-pregnancy and 18 months after delivery, was followed for 1,022,250 person-years for development of IBD, according to the Danish National Patient Register. Associations were tested by Cox regression.
Results
Overweight subjects (25≤BMI<30 kg/m2) had the lowest risk of CD, whereas obesity (BMI≥30kg/m2) increased the risk of CD at all ages, and low BMI (BMI<18.5kg/m2) associated with CD diagnosed at age 18-<40 years. Hence, using normal weight subjects as the reference, adjusted HRs for risk of developing CD (at age 18-<40 years) were 1.8(95%CI, 0.9–3.7) for underweight, 0.6(0.3–1.2) for overweight, and 1.5(0.8–2.7) for obese individuals (pre-pregnancy BMI). HRs were greater for BMI determined 18 months after delivery. Splines for CD risk according to waist:height ratio confirmed a U-shaped relationship with CD occurring <40 years, and a linear relationship with CD diagnosed at age 40+. There was no relationship between BMI and risk of UC.
Conclusion
For the first time, we demonstrate that both high BMI and low BMI are risk factors for CD. Underweight may be a pre-clinical manifestation of disease being present many years before onset with obesity being a true risk factor. This raises the question as to whether there may be two distinct forms of CD.
... [10] Both ghrelin and leptin have been implicated in studies as potential mediators of inflammation in IBD, as one study by Karmiris et al. shows. [11] The aim of this study is to determine if there is any difference between the plasma ghrelin and leptin levels in patients with IBD (active and inactive) compared to controls and their association with the nutritional status in both. This study may highlight the importance of ghrelin and leptin concentration in IBD patients as disease markers in those patients. ...
... Ghrelin is not a adipokine, but has a regulatory effect within the immune system, as it is mutually expressed with leptin. Ghrelin exerts multiple immunoregulatory effects by antagonizing leptin [11]. Studies on circulating adiponectin, visfatin, and ghrelin levels in patients with SLE compared to healthy controls have shown mixed results [12][13][14][15][16][17][18][19][20][21][22]. ...
... [10] Both ghrelin and leptin have been implicated in studies as potential mediators of inflammation in IBD, as one study by Karmiris et al. shows. [11] The aim of this study is to determine if there is any difference between the plasma ghrelin and leptin levels in patients with IBD (active and inactive) compared to controls and their association with the nutritional status in both. This study may highlight the importance of ghrelin and leptin concentration in IBD patients as disease markers in those patients. ...
... Adiponectin, which is inversely affected by obesity and shows a structure similar to TNF-↵, has been proposed to antagonize that proinflammatory cytokine by competing with the TNF-↵ receptor [53][54][55][56]. There are conflicting results related to the circulating levels of adiponectin in patients with IBD [48,50,54,[57][58][59][60][61]. However, recent studies demonstrated that lower levels of serum and mesenteric adiponectin in active CD patients clearly suggest a defective regulation of that anti-inflammatory adipokine's pathway in the pathogenesis of CD [53]. ...
Inflammatory bowel diseases (IBDs) are a heterogeneous group of disorders exhibited by two major phenotypic forms: Crohn‘s disease and ulcerative colitis. Although the aetiology of IBD is unknown, several factors coming from the adipose tissue and skeletal muscles, such as cytokines, adipokines and myokines, were suggested in the pathogenesis of ulcerative colitis; however, it has not been extensively studied whether voluntary exercise can ameliorate that disorder. We explored the effect of moderate exercise (i.e., voluntary wheel running) on the disease activity index (DAI), colonic blood flow (CBF), plasma irisin and adiponectin levels and real-time PCR expression of proinflammatory markers in mesenteric fat in mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis fed a high-fat diet (HFD) compared to those on a standard chow diet (SD). Macroscopic and microscopic colitis in sedentary SD mice was accompanied by a significant fall in CBF, some increase in colonic tissue weight and a significant increase in the plasma levels of tumour necrosis factor-alpha (TNF-α), IL-6, monocyte chemotactic protein 1 (MCP-1) and IL-13 (p < 0.05). In sedentary HFD mice, colonic lesions were aggravated, colonic tissue weight increased and the plasma TNF-α, IL-6, MCP-1, IL-1β and leptin levels significantly increased. Simultaneously, a significant decrease in the plasma irisin and adiponectin levels was observed in comparison with SD mice (p < 0.05). Exercise significantly decreased macroscopic and microscopic colitis, substantially increased CBF and attenuated the plasma TNF-α, IL-6, MCP-1, IL-1β and leptin levels while raising the plasma irisin and the plasma and WAT concentrations of adiponectin in HFD mice (p < 0.05). We conclude that: (1) experimental colitis is exacerbated in HFD mice, possibly due to a fall in colonic microcirculation and an increase in the plasma and mesenteric fat content of proinflammatory biomarkers; and (2) voluntary physical activity can attenuate the severity of colonic damage in mice fed a HFD through the release of protective irisin and restoration of plasma adiponectin.
... As a result, it was found that higher resistin levels were present in sepsis and other inflammatory diseases. 38,39 It is thought that the role of resistin in this process is that it plays a role in systemic inflammatory response through a potent reciprocal interaction with cytokines such as TNF-α, IL-6, and IL-10 which play a role in the regulation of systemic inflammatory response, angiogenesis, cellular proliferation, differentiation, and migration. 39 There are limited number of studies investigating the relationship between resistin and cancer. ...
INTRODUCTION
Cancer cachexia is one of the most frequent effects of malignancy, is often associated with poor prognosis, and may account for up to 20% of cancer deaths. The aim of our study was to evaluate the relationship of cancer cachexia and serum levels of resistin and leptin in patients with advanced non–small cell lung cancer.
METHODS
A total of 67 chemotherapy-naïve patients with advanced-stage non–small cell cancer and a control group containing 20 healthy individuals without a known chronic disease were enrolled in this study. All individuals in the control group were age and sex matched. Demographic, anthropometric, laboratory data and serum levels of adipokines were measured for 2 groups. Progression-free survival and overall survival were estimated using the Kaplan-Meier method. Survival among various factors was calculated using the log-rank test.
RESULTS
Patients presented significantly higher serum resistin (P = .0001) and lower serum leptin levels (P = .025) than the control group. Lower serum levels of leptin were correlated with overall survival (P = .011).
CONCLUSIONS
Serum leptin and resistin levels play key role as proinflammatory cytokines in lung cancer and cancer cachexia; however, their use as diagnostic or prognostic markers is not possible yet, and further large-scale studies are required to confirm our findings.
... Inflammation: activity [50]. Leptin indeed has structural and functional similarities with IL-6; it can stimulate the proliferation of blood mononuclear cells, increase the proliferation and the survival of CD4 T cells, stimulate the development of Th1 response, and promote dendritic cell differentiation via the activation of intracellular JAK-STAT pathways [51,52]. Another adipokine hyperexpressed in mesenteric fat in Crohn's disease is resistin. ...
Malnutrition is a major complication of inflammatory bowel disease (IBD). This mini review is focusing on main determinants of malnutrition in IBD, the most important components of malnutrition, including lean mass loss and sarcopenia, as an emerging problem. Each one of these components needs to be well considered in a correct nutritional evaluation of an IBD patient in order to build a correct multidisciplinary approach. The review is then focusing on possible instrumental and clinical armamentarium for the nutritional evaluation.
... Patients with active IBD show elevated levels of proinflammatory markers including tumor necrosis factor-α, interleukin-6, leptin, and neuropeptides [25,36]. Obesity also increases serum or tissue levels of these inflammatory mediators [16,30,37]. ...
Backgrounds:
With increased prevalence of obesity, the number of inflammatory bowel disease (IBD) patients suffering from morbid obesity has raised. It is not clear yet if bariatric surgery is a safe and effective option in this population.
Objectives:
Our systematic review aims to summarize the available literature on the safety and efficacy of bariatric surgery in morbidly obese patients with IBD.
Setting:
University hospital, Iran.
Methods:
A PubMed/MEDLINE search was performed to identify studies reporting the outcome of morbidly obese IBD patients. Postoperative outcome of IBD patients after bariatric surgery were pooled for early and late complications, change of IBD status, and medication alteration.
Results:
A total of 7 studies reported post-bariatric surgery outcomes of 43 morbidly obese IBD patients (31 females, 11 males) with an age ranging from 30 to 64 years and a body mass index from 35.7 to 71 kg/m(2). Of these, 25 suffered Crohn's disease (CD) (58.2%) and 18 were ulcerative colitis (UC) patients (41.8%). The small bowel was the most common involved gastrointestinal segment in 27.3% of patients. CD patients more commonly underwent sleeve gastrectomy (72%), while UC patients similarly underwent sleeve gastrectomy and Roux-en-Y gastric bypass (44.4%). After a follow-up of 8 to 77 months, IBD patients lost up to 71.4%±5.9% of excess weight and 14.3 kg/m(2)±5.7 kg/m(2) of body mass index. There were 9 early (21.4%) and 10 late (23.8%) postoperative complications related to the bariatric procedure. IBD remitted in 20 patients (47.6%), improved in 2 patients (4.8%), but exacerbated in 7 patients (16.7%).
Conclusions:
Although available data on morbidly obese patients with IBD is scarce, bariatric surgery seems to be a safe and effective option for these patients with no added morbidity or mortality. Further studies are necessary to confirm this data.
... Table 2. Serum biomarkers in IBD levels: elevation in comparison with healthy controls, correlation with disease activity according to CDAI, SCCAI, or endoscopic activity, modulation by effective treatment, and outcome of structural damage. [145,146,148,149,184] Ghrelin* + + + +/− [139][140][141]146] Resistin* + +/− + N A [ 142,143,146,149] Vaspin [ 150,151] S100A8/A9 + NA NA + [152][153][154][155] LCN-2 + + NA NA [166][167][168] hBD-2* − − NA NA [169,170] β2-M + + NA NA [171,172] ASCA + + − + [ 173,175,177,178,181,182] pANCA + − + − [173][174][175][176][177][178]181,182] ASCA: anti-saccharomyces cerevisiae antibodies; β2-M: β2-microglobulin; CDAI: Crohn's disease activity index; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; hBD-2: human beta-defensin-2; HNP: human neutrophil peptides; IL: interleukin; LCN-2: lipocalin-2; NA: not applicable; pANCA: perinuclear antineutrophil cytoplasmic antibodies; SCCAI: simple clinical colitis activity index; VCAM: vascular cell adhesion molecule; VEGF: vascular endothelial growth factor. *Plasma and serum. ...
Introduction: Early diagnosis, monitoring of disease activity, prediction of treatment response, and structural outcome remain major challenges in spondyloarthritis (SpA). Biomarkers could play a role in addressing these challenges, but in SpA there is a lack of suitable biomarkers.
Areas covered: As SpA is clinically and pathophysiologically closely related to psoriasis and inflammatory bowel disease (IBD), we reviewed in literature, the value of serum biomarkers in these conditions with the aim to find potential candidates for assessing SpA.
Expert commentary: Candidates of interest were antimicrobial peptides, including serum human beta defensin-2 (hBD-2) and lipocalin-2 (LCN-2), and class-1 MHC molecule beta2-microglobulin. Since these biomarkers are relevant in psoriasis and/or IBD from a pathophysiological point of view, and may play a role in the pathogenesis of SpA, we recommend further exploration of their value as biomarker in the diagnosis and prognosis of SpA.
... Individuals who consume less dietary fiber, raw fruits and vegetables tend to have higher predilection for IBD [44]. Meanwhile, molecular studies have linked adipose tissue to intestinal inflammation [45,46]. However, it remains unclear if this translates into a causal or clinically meaningful association between obesity and CD. ...
Inflammatory bowel disease (IBD) is characterized by two partially distinct alimentary disease processes, namely Crohn’s disease (CD) and ulcerative colitis (UC), affecting genetically predisposed individuals. CD and UC were first described in 1932 and 1859, respectively. It is estimated that 1.5 million in North America and 2.5 million persons in Europe have IBD. The peak incidence of CD and UC is between 20–30 years and 30–40 years of age, respectively. Both incidence and prevalence of CD and UC are similar across males and females. However, several studies suggest a female predominance in CD and a male predominance in UC. The pathogenesis of IBD is attributed to an uncontrolled immune-mediated inflammatory response to an unrecognized environmental trigger that interacts with the intestinal flora. Various determinants of IBD include the following: peculiar environmental triggers, intestinal immune mechanisms, heritable factors, gut flora, diet, mesenteric fat, medications, nicotine, infectious agents, immunization, hygiene, pregnancy, breastfeeding, stress and lifestyle. Predominant complications in IBD are surgery, malnutrition, disease exacerbations and cancer. Patients with CD have a higher mortality compared to general population. Epidemiological studies continue to expand our understanding of the distribution, determinants and mechanisms of IBD. This has enabled us to recognize safer and effective approaches to management.
... Resting energy expenditure has been shown to be increased during acute flares in CD and proinflammatory cytokines exert an anorexic effect [5]. The inflammatory state in IBD has been linked to alterations in the levels of a number of metabolic hormones including leptin, adiponectin, and ghrelin which can affect satiety [6]. Secondly, these disease processes are associated with malabsorption of both macronutrients and micronutrients [7]. ...
Aims. To identify prevalence, severity, and environmental determinants of weight loss in inflammatory bowel disease (IBD) patients just prior to time of formal diagnosis. Methodology. IBD patients attending outpatient clinic were questioned about weight loss prior to diagnosis and other environmental and demographic variables. The percentage BMI loss was calculated for each subject and factors associated with weight loss were determined. Results. Four hundred and ninety-four subjects were recruited (237 cases of Crohn’s disease (CD) and 257 cases of ulcerative colitis (UC)). Overall, 57% of subjects with CD and 51% of subjects with UC experienced significant weight loss prior to diagnosis (>5% BMI loss). Younger age at diagnosis and history of previous IBD surgery were significantly associated with both lower BMI at diagnosis and increased weight loss prior to diagnosis. In CD patients, increasing age at diagnosis was inversely associated with weight loss prior to diagnosis. Ileal disease was a risk factor of weight loss, whereas prior appendectomy was associated with reduced risk of weight loss. Conclusions. Weight loss is a significant problem for many IBD patients at presentation, especially in younger age and CD with ileal involvement. Appendectomy is associated with diminished weight loss.
... It acts as a pro-inflammatory factor that increases the production of inflammatory cytokines and elevates the expression of cell adhesion molecules. While its exact biologic functions are still being elucidated, higher resistin levels have been associated with chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, and resistin may play a role in the pathophysiology of atherosclerosis and endothelial cell injury [86, 87]. ...
In the last two decades, perceptions about the role of body fat have changed. Adipocytes modulate endocrine and immune homeostasis
by synthesizing hundreds of hormones, known as adipocytokines. Many studies have been investigating the influences and effects
of these adipocytokines and suggest that they are modulated by the nutritional and immunologic milieu. Kidney transplant recipients
(KTRs) are a unique and relevant population in which the function of adipocytokines can be examined, given their altered nutritional
and immune status and subsequent dysregulation of adipocytokine metabolism. In this review, we summarize the recent findings
about four specific adipocytokines and their respective roles in KTRs. We decided to evaluate the most widely described adipocytokines,
including leptin, adiponectin, visfatin and resistin. Increasing evidence suggests that these adipocytokines may lead to cardiovascular
events and metabolic changes in the general population and may also increase mortality and graft loss rate in KTRs. In addition,
we present findings on the interrelationship between serum adipocytokine levels and nutritional and immunologic status, and
mechanisms by which adipocytokines modulate morbidity and outcomes in KTRs.
Atypical antipsychotics (AAPs) are commonly prescribed drugs in the treatment of schizophrenia, bipolar disorder and other mental diseases with psychotic traits. Although the use of AAPs is associated with beneficial effects in these patients, they are also associated with undesired metabolic side effects, including metabolic syndrome (MetS). MeS is defined by the presence of metabolic abnormalities such as large waist circumference, dyslipidemia, fasting hyperglycemia and elevated blood pressure, which predispose to type 2 diabetes (T2D) and cardiovascular disease. In this review, the molecular and cellular mechanisms involved in these undesired metabolic abnormalities induced by AAPs will be described. These mechanisms are complex, as AAPs have multiple cellular targets, significantly affecting the activities of several hormones and neuromodulators. Additionally, AAPs affect all the relevant metabolic organs, namely the liver, pancreas, adipose tissue, skeletal muscle and intestine, and the central and peripheral nervous system as well. A better undertanding of the molecular targets linking AAPs with MetS and of the mechanisms responsible for clinically different side effects of distinct AAPs is needed. This knowledge will help in the development of novel AAPs with less adverse effects as well as of adjuvant therapies to patients receiving AAPs.
This article is protected by copyright. All rights reserved.
Inflammatory bowel disease (IBD) is a chronic, relapsing gastrointestinal (GI) disorder characterized by intestinal inflammation. The etiology of IBD is multifactorial and results from a complex interplay between mucosal immunity, environmental factors, and host genetics. Future therapeutics for GI disorders, including IBD, that are driven by oxidative stress require a greater understanding of the cellular and molecular mechanisms mediated by reactive oxygen species (ROS). In the GI tract, oxidative stressors include infections and pro-inflammatory responses, which boost ROS generation by promoting the production of pro-inflammatory cytokines. Nuclear factor kappa B (NF-kB) and nuclear factor erythroid 2-related factor 2 (Nrf2) represent two important signaling pathways in intestinal immune cells that regulate numerous physiological processes, including anti-inflammatory and antioxidant activities. Natural antioxidant compounds exhibit ROS scavenging and increase antioxidant defense capacity to inhibit pro-oxidative enzymes, which may be useful in IBD treatment. In this review, we discuss various polyphenolic substances (such as resveratrol, curcumin, quercetin, green tea flavonoids, caffeic acid phenethyl ester, luteolin, xanthohumol, genistein, alpinetin, proanthocyanidins, anthocyanins, silymarin), phenolic compounds including thymol, alkaloids such as berberine, storage polysaccharides such as tamarind xyloglucan, and other phytochemicals represented by isothiocyanate sulforaphane and food/spices (such as ginger, flaxseed oil), as well as antioxidant hormones like melatonin that target cellular signaling pathways to reduce intestinal inflammation occurring with IBD.
Introduction:
Adipose tissue plays an important role in the pathogenesis of inflammatory conditions. The role of adipokines in inflammatory bowel disease (IBD) has been evaluated in the current literature with conflicting results. The aim of this study was to evaluate adiponectin levels in IBD patients, including Crohn's disease (CD) and ulcerative colitis (UC), compared to controls, as well as further subgroup analyses. Hence, assessing the potential role of adiponectin as a surrogate marker.
Methods:
We performed a systematic electronic search on PubMed, EMBASE, Scopus and Cochrane Library, including observational or interventional studies evaluating serum or plasma adiponectin levels in IBD patients on humans. The primary summary outcome was the mean difference (MD) in serum or plasma adiponectin levels between IBD patients vs. controls. Subgroups analyses were conducted involving adiponectin levels in CD and UC compared to controls, as well as CD compared to UC.
Results:
A total of 20 studies were included in our qualitative synthesis and 14 studies in our quantitative synthesis, with a total population sample of 2,085 subjects. No significant MD in serum adiponectin levels was observed between IBD patients vs. controls (-1.331 [95% CI -3.135-0.472]), UC patients vs. controls (-0.213 [95% CI -1.898-1.472]), and CD patients vs. controls (-0.851 [95% CI -2.263-0.561]). Nevertheless, a significant MD was found between UC patients vs. CD patients (0.859 [95% CI 0.097-1.622]).
Conclusions:
Serum adiponectin levels were not able to differentiate between IBD, UC and CD patients compared to controls. However, significantly higher serum adiponectin levels were observed in UC compared to CD patients.
The development and anatomy of the mesentery were recently clarified. The mesentery is the organ in and on which all abdominal digestive organs develop and then remain directly connected to. In turn, this leads to a clarification of the organisation of the abdomen in the Mesenteric Model of Abdominal Anatomy. According to that model, all organs of the abdomen are organised into one of two discrete anatomical domains. The mesenteric domain contains all abdominal digestive organs positioned on the mesenteric frame. The non-mesenteric domain comprises all genitourinary organs positioned on the musculoskeletal mainframe of the abdomen. All abdominal disease follows the Mesenteric Model in terms of its distribution. Inflammation accounts for many of the manifestations of abdominal disease (i.e. peritonism, collections, abscess formation) and the anatomical distribution of inflammation (as well as its consequences) is explained by this model and not by conventional models of abdominal anatomy. Thus, it is essential to clarify the development and anatomy of the mesentery, and the implications these have for our understanding of the organisation of the abdomen.KeywordsMesenteryDevelopmentAnatomyMesenteric model of abdominal anatomy
Characterized by chronic intestinal inflammation, Crohn’s disease patients frequently suffer from complications of intestinal fibrostenosis. In recent years, the mesenteric inflammation in Crohn’s disease and the formation of distinctive creeping fat have gained increasing attention. Clinically, creeping fat and intestinal strictures are often observed to co-occur in the same intestinal segment. Creeping fat secretes cytokines and adipokines in increasing amounts compared to healthy mesenteric fat that interact with adjacent tissues, suggesting that the relationship between creeping fat and intestinal fibrosis is far more complex than we previously thought. This chapter will briefly outline the relationship between mesenteric inflammation and intestinal fibrosis, and provide a future outlook on the potential treatment of intestinal fibrosis.KeywordsCrohn’s diseaseIntestinal fibrosisCreeping fatMesenteric inflammation
Background:
The present study aimed to investigate the serum and salivary ghrelin and cortisol levels in smokers and non-smokers with Stage III Periodontitis.
Methods:
The present study comprised of a total of 90 systemically healthy patients categorized in three groups: Group I- Periodontally healthy patients; Group II- Non-smokers with Stage III Periodontitis and Group III- Smokers with Stage III periodontitis. Clinical parameters of Probing pocket depth (PPD), Clinical attachment levels (CAL), Plaque Index (PI), Gingival Index (GI) and Papillary Bleeding Index (PBI)were recorded and biochemical parameters of serum and salivary ghrelin and cortisol levels were analyzed via Enzyme Linked Immunosorbent Assay (ELISA). Stress levels were assessed using Zung's self-rating depression scale.
Results:
Serum and salivary ghrelin values were found to be higher in Group II (620.25 ± 260.86 pg/ml, 892.40 ± 271.65 pg/ml respectively) as compared to Group III. Similarly, salivary as well as serum cortisol levels were higher in Group III (20.78 ± 9.23 pg/ml, 399.37 ±189.21 pg/ml respectively) as compared to Group II (16.36 ± 8.88 pg/ml, 320.68 ± 107.01 pg/ml respectively). In Group III, a direct correlation was observed between stress, serum and salivary cortisol levels while an inverse correlation was found between stress, serum and salivary ghrelin levels. Group III showed a greater number of depressed patients followed by Group II and I.
Conclusion:
As per the results smokers with Stage III Periodontitis exhibit an elevated stress and cortisol levels, lower serum and salivary ghrelin levels as compared to the non-smokers. This article is protected by copyright. All rights reserved.
In the last decade, there has been growing interest in the pathological involvement of hypertrophic mesenteric fat attached to the serosa of the inflamed intestinal segments involved in Crohn's disease, known as creeping fat. In spite of its protective nature, creeping fat harbours an aberrant inflammatory activity which, in an already inflamed intestine, may explain why creeping fat is associated with a greater severity of Crohn’s disease. The transmural inflammation of Crohn’s disease facilitates the interaction of mesenteric fat with translocated intestinal microorganisms, contributing to the activation of the immune response. This may be not the only way in which microorganisms alter the homeostasis of this fatty tissue: intestinal dysbiosis may also impair xenobiotic metabolism. All these Crohn’s disease-related alterations have a functional impact on nuclear receptors such as the farnesoid X receptor or the peroxisome proliferator-activated receptor γ, which are implicated in the regulation of immune response, adipogenesis and the maintenance of barrier function, as well as on the creeping fat production of inflammatory influencers such as adipokines. The dysfunction of creeping fat worsens the inflammatory course of Crohn’s disease and may favour intestinal fibrosis and fistulizing complications. However, our current knowledge of the pathophysiology and pathogenic role of creeping fat is controversial and a better understanding might provide new therapeutic targets for Crohn’s disease. We aim to review and update the key cellular and molecular alterations involved in this inflammatory process that link the pathological components of Crohn’s disease with the development of creeping fat.
Leptin is over-secreted in many autoimmune diseases, which can promote dendritic cells (DCs) maturation and up-regulate the expression of inflammatory cytokines, but the underlying mechanisms are not fully elucidated. Considering the major role of leptin in maintaining energy balance and the significant role of glycolysis in DCs activation, our study aims to investigate whether leptin promotes the activation of DCs via glycolysis and its underlying mechanisms. We demonstrated that leptin promoted the activation of DCs, including up-regulating the expression of co-stimulatory molecules and inflammatory cytokines, enhancing the proliferation and T helper 17 (Th17) cell ratio in peripheral blood mononuclear cells (PBMC) co-cultured with leptin-stimulated DCs. Leptin also enhanced DCs glycolysis with increased glucose consumption, lactate production, and the expression of hexokinase 2 (HK2). In addition, the activation of DCs stimulated by leptin could be inhibited by the glycolysis inhibitor 2-deoxy-D-glucose (2-DG). To explore the signaling pathways involved in leptin-induced HK2 expression, we observed that the inhibitors of STAT3 (NSC74859) could repress the enhancement of HK2 triggered by leptin stimulation. Therefore, our results indicated that leptin promoted glycolytic metabolism to induce DCs activation via STAT3-HK2 pathway.
Besides its function controlling energy expenditure and food intake, leptin is an important modulator of inflammatory responses. The role of leptin in intestinal inflammation remains controversial, since both pro-inflammatory and anti-inflammatory effects have been reported. This study was carried out to further understand leptin contribution in the inflamed intestinal mucosa. Exogenous PEG-leptin or saline solution was given to C57BL/6 mice for two weeks. After 1 week, acute colitis was induced to C57BL/6 mice using dextran sulfate sodium (DSS) in drinking water. The severity of colitis, inflammatory parameters and mucosal barrier function were evaluated. Overall our results indicate that colitis was less severe in mice receiving leptin, as shown by a decrease in rectal bleeding, epithelial damage and colon inflammatory markers, and improved diarrhea. Leptin-treated mice displayed an increase in the expression of tight junction proteins and proliferative expression markers in colon, indicating a reinforcement in the mucosal barrier function induced by leptin administration. PEG-leptin treatment conferred protection to mice in the DSS model of colitis by reinforcing mucosal barrier function.
Background/Aims: Ghrelin and leptin are thought to play a role in the loss of appetite in active inflammatory bowel disease (IBD). This study seeks to probe into the association of these markers with regards to IBD and the nutritional status of these patients. A case-control study was conducted between May 2015 and March 2016 at King Khalid University Hospital (KKUH). Thirty-one patients with IBD (both active and non-active) and forty-one healthy controls (both non-fasting and fasting) were recruited.
Patients and Methods: Plasma ghrelin and leptin levels were determined using an enzyme immunoassay (EIA) technique. The nutritional status was determined through the standardized Mini-Nutritional Assessment (MNA) questionnaire.
Results: The difference in the plasma ghrelin between active (263.7 pg/mL) and non-active (108 pg/mL) cases was significant (P= 0.02). The difference in mean plasma leptin level between active cases (229.4 pg/mL) vs. non-active cases (359.7 pg/mL) was insignificant (P= 0.4). In fasting (2028.6 pg/mL) and non-fasting controls (438.8 pg/mL), the mean plasma ghrelin values was significantly different (P< 0.01). In contrast, the plasma leptin level difference between fasting (727.3 pg/mL) and non-fasting (577 pg/mL) controls was insignificant (P= 0.14). There is a statistically significant association in mean ghrelin levels between the case group and the control group (P< 0.01). With regards to nutritional status, the mean MNA score of active cases compared to fasting controls was 18.8 ± 5 vs. 20.8 ± 3.8, respectively (P< 0.01)
Conclusion: Ghrelin levels were lower in the active IBD cases compared to the inactive ones, signifying an underlying pathology as etiology to this phenomenon. Furthermore, ghrelin levels were significantly lower in both case groups compared to the controls. These findings, along with the disparity in the MNA scores, insinuate a possible link between hormone levels and the loss of appetite from which these patients suffer.
The mechanisms that balance food intake and energy expenditure determine who will be obese and who will be lean. One of the molecules that regulates energy balance in the mouse is the obese (ob) gene. Mutation of ob results in profound obesity and type II diabetes as part of a syndrome that resembles morbid obesity in humans. The ob gene product may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot.
Obesity is associated with an increased incidence of infection, diabetes, and cardiovascular disease, which together account for most obesity-related morbidity and mortality. Decreased expression of leptin or of functional leptin receptors results in hyperphagia, decreased energy expenditure, and obesity. It is unclear, however, whether defective leptin-dependent signal transduction directly promotes any of the conditions that frequently complicate obesity. Abnormalities in tumor necrosis factor alpha expression have been noted in each of the above comorbid conditions, so leptin deficiency could promote these complications if leptin had immunoregulatory activity. Studies of rodents with genetic abnormalities in leptin or leptin receptors revealed obesity-related deficits in macrophage phagocytosis and the expression of proinflammatory cytokines both in vivo and in vitro. Exogenous leptin up-regulated both phagocytosis and the production of proinflammatory cytokines. These results identify an important and novel function for leptin: up-regulation of inflammatory immune responses, which may provide a common pathogenetic mechanism that contributes to several of the major complications of obesity.
Although leptin, an adipocyte derived hormone which regulates food intake and energy balance, is released after injections of tumour necrosis factor (TNF) and interleukin 1, plasma concentrations have not been characterised in chronic inflammation. Leptin may contribute to the anorexia and body weight loss associated particularly with the acute stages of inflammatory bowel disease.
To investigate plasma leptin concentrations during the time course of intestinal inflammation in different animal models.
Plasma leptin was measured at different time points in rats with trinitrobenzene sulphonic acid (TNBS) induced colitis, indomethacin induced ileitis, or endotoxic shock caused by lipopolysaccharide (LPS). Systemic TNF-alpha was also measured during acute inflammation.
Plasma leptin concentrations increased fourfold eight hours after induction of TNBS colitis (p<0.0001) and twofold after administration of ethanol alone (p<0.02). Plasma leptin responses throughout the first post-treatment day were correlated with myeloperoxidase activity and gross damage scores. Similar leptin overexpression was observed in indomethacin induced ileitis and in rats with endotoxic shock. Plasma concentrations were lower in TNBS treated rats than in controls on day 5 before reaching a similar concentration on day 14. Anorexia and body weight loss were observed during the first four days post-TNBS. A significant increase in systemic TNF-alpha was only detected in LPS treated rats.
Elevated plasma leptin concentrations, correlated with the degree of inflammation and associated with anorexia, were induced in rats during the early stages of experimental intestinal inflammation but proved transient; this might account for discrepancies in recent results concerning concentrations in patients with inflammatory bowel diseases.
We investigated the functions of adiponectin, an adipocyte-specific secretory protein and a new member of the family of soluble defense collagens, in hematopoiesis and immune responses. Adiponectin suppressed colony formation from colony-forming units (CFU)-granulocyte-macrophage, CFU-macrophage, and CFU-granulocyte, whereas it had no effect on that of burst-forming units-erythroid or mixed erythroid-myeloid CFU. In addition, adiponectin inhibited proliferation of 4 of 9 myeloid cell lines but did not suppress proliferation of erythroid or lymphoid cell lines except for one cell line. These results suggest that adiponectin predominantly inhibits proliferation of myelomonocytic lineage cells. At least one mechanism of the growth inhibition is induction of apoptosis because treatment of acute myelomonocytic leukemia lines with adiponectin induced the appearance of subdiploid peaks and oligonucleosomal DNA fragmentation. Aside from inhibiting growth of myelomonocytic progenitors, adiponectin suppressed mature macrophage functions. Treatment of cultured macrophages with adiponectin significantly inhibited their phagocytic activity and their lipopolysaccharide-induced production of tumor necrosis factor alpha. Suppression of phagocytosis by adiponectin is mediated by one of the complement C1q receptors, C1qRp, because this function was completely abrogated by the addition of an anti-C1qRp monoclonal antibody. These observations suggest that adiponectin is an important negative regulator in hematopoiesis and immune systems and raise the possibility that it may be involved in ending inflammatory responses through its inhibitory functions. (Blood. 2000;96:1723-1732)
Diabetes mellitus is a chronic disease that leads to complications including heart disease, stroke, kidney failure, blindness and nerve damage. Type 2 diabetes, characterized by target-tissue resistance to insulin, is epidemic in industrialized societies and is strongly associated with obesity; however, the mechanism by which increased adiposity causes insulin resistance is unclear. Here we show that adipocytes secrete a unique signalling molecule, which we have named resistin (for resistance to insulin). Circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment. Resistin is thus a hormone that potentially links obesity to diabetes.
We have identified a family of resistin-like molecules (RELMs) in rodents and humans. Resistin is a hormone produced by fat cells. RELMalpha is a secreted protein that has a restricted tissue distribution with highest levels in adipose tissue. Another family member, RELMbeta, is a secreted protein expressed only in the gastrointestinal tract, particularly the colon, in both mouse and human. RELMbeta gene expression is highest in proliferative epithelial cells and is markedly increased in tumors, suggesting a role in intestinal proliferation. Resistin and the RELMs share a cysteine composition and other signature features. Thus, the RELMs together with resistin comprise a class of tissue-specific signaling molecules.
It is well known that leptin, the ob gene product, is involved in the regulation of food intake and thermogenesis. Recent studies also demonstrate that leptin may be able to modulate functions of cells involved in nonspecific immune response such as phagocytosis and secretion of cytokines by macrophages. This and the prominent implication of polymorphonuclear neutrophils (PMNs) in infectious response suggested a possible role of leptin as a modulator of PMN functions. We detected a leptin receptor on the PMN membrane by immunocytochemistry with an anti-leptin receptor. Using chemiluminescence we then demonstrated that leptin enhances oxidative species production by stimulated PMNs. These results show for the first time that a functional leptin receptor is present on PMNs and that leptin may be able to influence their oxidative capacity.
Leptin is capable of modulating the immune response. Proinflammatory cytokines induce leptin production, and we now demonstrate that leptin can directly activate the inflammatory response. RNA expression for the leptin receptor (Ob-R) was detectable in human PBMCs. Ob-R expression was examined at the protein level by whole blood flow cytometry using an anti-human Ob-R mAb 9F8. The percentage of cells expressing leptin receptor was 25 +/- 5% for monocytes, 12 +/- 4% for neutrophils, and 5 +/- 1% for lymphocytes (only B lymphocytes). Incubation of resting PBMCs with leptin induced rapid expression of TNF-alpha and IL-6 mRNA and a dose-dependent production of TNF-alpha and IL-6 by monocytes. Incubation of resting PBMCs with high-dose leptin (250 ng/ml, 3-5 days) induced proliferation of resting cultured PBMCs and their secretion of TNF-alpha (5-fold), IL-6 (19-fold), and IFN-gamma (2.5-fold), but had no effect on IL-4 secretion. The effect of leptin was distinct from, and additive to, that seen after exposure to endotoxin or activation by the mixed lymphocyte reaction. In conclusion, Ob-R is expressed on human circulating leukocytes, predominantly on monocytes. At high doses, leptin induces proinflammatory cytokine production by resting human PBMCs and augments the release of these cytokines from activated PBMCs in a pattern compatible with the induction of Th1 cytokines. These results demonstrate that leptin has a direct effect on the generation of an inflammatory response. This is of relevance when considering leptin therapy and may partly explain the relationship among leptin, proinflammatory cytokines, insulin resistance, and obesity.
Ghrelin was recently isolated from the rat stomach as an endogenous ligand for the growth-hormone secretagogue receptor (GHS-R) and is known to exist in the gastrointestinal tract and hypothalamus. In this study, we investigated in detail the distribution and morphologic characteristics of ghrelin-containing cells (ghrelin cells) in the gastrointestinal tract by immunohistochemistry and in situ hybridization. Ghrelin cells were found to be localized in the mucous membrane of the stomach, duodenum, ileum, cecum and colon but not in myenteric plexus, and they can be classified into open- and closed-type cells. The greatest number of ghrelin cells was found in the stomach, and it was found that the number of the opened-type cells gradually increased in the direction from stomach to the lower gastrointestinal tract. These results suggest that the two types of ghrelin cells may be distinctly regulated and play different physiological roles in various regions of the gastrointestinal tract.
Leptin, a hormone mainly produced by fat cells, acts primarily on the hypothalamus regulating energy expenditure and food intake. Leptin receptors are expressed in several tissues and the possible physiological role of leptin is being extensively investigated, with the result that important peripheral actions of the hormone in the organism are being discovered. Recent studies have demonstrated leptin and leptin receptor expression in gastric epithelial cells. In the present study, we report the presence of the long leptin receptor isoform (OB-Rb) in human, rat, and mouse small intestine, supporting the hypothesis of leptin as a hormone involved in gastrointestinal function.
The presence of the leptin receptor was determined by immunocytochemical methods using antibodies against the peptide corresponding to the carboxy terminus of the long isoform of the leptin receptor. Human duodenal biopsies from normal individuals undergoing gastrointestinal endoscopy, and intestinal fragments of Wistar rats and Swiss mice were processed for the study.
Immunoreactivity for the long leptin receptor isoform was observed in the three studied species. Staining was located throughout the cytoplasm of the enterocytes, of both villi and crypts, and in the basolateral plasma membrane. Immunolabelling for OB-Rb protein was also found in the brush border of human enterocytes of formol and paraformaldehyde fixed samples.
This report demonstrates the presence of the long leptin receptor isoform in the absorptive cells of rat, mouse, and human small intestine, suggesting that leptin could have a physiological role in the regulation of nutrient absorption.
Ghrelin is a novel growth hormone-releasing peptide, originally identified in the rat stomach as the endogenous ligand for the growth hormone secretagogue-receptor (GHS-R1a). Ghrelin is involved in the regulation of GH release, but it has recently been suggested that ghrelin may have other actions, including effects on appetite, carbohydrate metabolism, heart, kidney, pancreas, gonads, and cell proliferation. The distribution of ghrelin, its functional receptor (type 1a) and the unspliced, non-functional GHS-R type 1b mRNA expression was investigated in various human tissues using classical and real-time reverse transcription and polymerase chain reaction. GHS-R1a was predominantly expressed in the pituitary and at much lower levels in the thyroid gland, pancreas, spleen, myocardium and adrenal gland. In contrast, ghrelin was found in the stomach, other parts of the gut and, indeed, in all the tissues studied (adrenal gland, atrium, breast, buccal mucosa, esophagus, Fallopian tube, fat tissue, gall bladder, human lymphocytes, ileum, kidney, left colon, liver, lung, lymph node, muscle, muscle, myocardium, ovary, pancreas, pituitary, placenta, prostate, right colon, skin, spleen, testis, thyroid, and vein). GHS-R1b expression was also widespread in all tissues studied. The significance of the widespread tissue distribution of ghrelin remains to be determined. These data suggest that ghrelin might have widespread physiological effects via different, partly unidentified, subtypes of the GHS-R in endocrine and non-endocrine tissues.
Preadipocytes are present throughout adult life in adipose tissues and can proliferate and differentiate into mature adipocytes according to the energy balance. An increasing number of reports demonstrate that cells from adipose lineages (preadipocytes and adipocytes) and macrophages share numerous functional or antigenic properties. No large scale comparison reflecting the phenotype complexity has been performed between these different cell types until now. We used profiling analysis to define the common features shared by preadipocyte, adipocyte, and macrophage populations. Our analysis showed that the preadipocyte profile is surprisingly closer to the macrophage than to the adipocyte profile. From these data, we hypothesized that in a macrophage environment preadipocytes could effectively be converted into macrophages. We injected labeled stroma-vascular cells isolated from mouse white adipose tissue or 3T3-L1 preadipocyte cell line into the peritoneal cavity of nude mice and investigated changes in their phenotype. Preadipocytes rapidly and massively acquired high phagocytic activity and index. 60-70% of preadipocytes also expressed five macrophage-specific antigens: F4/80, Mac-1, CD80, CD86, and CD45. These values were similar to those observed for peritoneal macrophages. In vitro experiments showed that cell-to-cell contact between preadipocytes and peritoneal macrophages partially induced this preadipocyte phenotype conversion. Overall, these results suggest that preadipocyte and macrophage phenotypes are very similar and that preadipocytes have the potential to be very efficiently and rapidly converted into macrophages. This work emphasizes the great cellular plasticity of adipose precursors and reinforces the link between adipose tissue and innate immunity processes.
Adiponectin is an adipose tissue-specific protein that is abundantly present in the circulation and suggested to be involved in insulin sensitivity and development of atherosclerosis. Because cytokines are suggested to regulate adiponectin, the aim of the present study was to investigate the interaction between adiponectin and three adipose tissue-derived cytokines (IL-6, IL-8, and TNF-alpha). The study was divided into three substudies as follows: 1) plasma adiponectin and mRNA levels in adipose tissue biopsies from obese subjects [mean body mass index (BMI): 39.7 kg/m2, n = 6] before and after weight loss; 2) plasma adiponectin in obese men (mean BMI: 38.7 kg/m2, n = 19) compared with lean men (mean BMI: 23.4 kg/m2, n = 10) before and after weight loss; and 3) in vitro direct effects of IL-6, IL-8, and TNF-alpha on adiponectin mRNA levels in adipose tissue cultures. The results were that 1) weight loss resulted in a 51% (P < 0.05) increase in plasma adiponectin and a 45% (P < 0.05) increase in adipose tissue mRNA levels; 2) plasma adiponectin was 53% (P < 0.01) higher in lean compared with obese men, and plasma adiponectin was inversely correlated with adiposity, insulin sensitivity, and IL-6; and 3) TNF-alpha (P < 0.01) and IL-6 plus its soluble receptor (P < 0.05) decreased adiponectin mRNA levels in vitro. The inverse relationship between plasma adiponectin and cytokines in vivo and the cytokine-induced reduction in adiponectin mRNA in vitro suggests that endogenous cytokines may inhibit adiponectin. This could be of importance for the association between cytokines (e.g., IL-6) and insulin resistance and atherosclerosis.
Leptin is a key mediator of signals regulating food intake and energy expenditure and exerts potent immunomodulatory effects. We investigated the mechanisms mediating the action of leptin on GH secretion from peripheral blood mononuclear cells (PBMCs). Using immunofluorescence microscopy, we demonstrated a polarized expression pattern of leptin receptor protein on the surface of mononuclear cells and constitutive expression of GH in PBMCs. Leptin exhibited a dose-dependent stimulatory effect on GH secretion by PBMCs and also up-regulated the GH receptor gene expression. We did not observe any additive effects of leptin on GH secretion upon activation of cells with the plant mitogen phytohemagglutinin, unlike leptin, phytohemagglutinin exerted no effect on GH receptor mRNA expression. Leptin led to a nitric oxide (NO) synthase (NOS)-specific, dose-dependent increase in NO production from PBMCs because leptin-induced NO release was blocked by the addition of the NOS inhibitor Nomega-Nitro-l-arginine methyl ester and protein kinase C (PKC) inhibitor calphostin C. This leptin-induced GH secretion was dependent on both PKC and NO activation because the addition of PKC and NOS inhibitors inhibited leptin-induced GH production. Although the addition of sodium nitroprusside, a spontaneous liberator of NO, stimulated GH release from PBMCs, leptin had no additive or synergistic effect on sodium nitroprusside-induced GH production. Together, these findings demonstrate a unique action of leptin on immune cells via its ability to stimulate the GH production by blood mononuclear cells via PKC- and NO-dependent pathways. These data also support a probable role for local immune-derived GH in mediating some of the pleiotropic actions of leptin.
Resistin, an adipocyte secreted factor, has been suggested to link obesity with type 2 diabetes in rodent models, but its relevance to human diabetes remains uncertain. Although previous studies have suggested a role for this adipocytokine as a pathogenic factor, its functional effects, regulation by insulin, and alteration of serum resistin concentration by diabetes status remain to be elucidated. Therefore, the aims of this study were to analyze serum resistin concentrations in type 2 diabetic subjects; to determine the in vitro effects of insulin and rosiglitazone (RSG) on the regulation of resistin, and to examine the functional effects of recombinant human resistin on glucose and lipid metabolism in vitro. Serum concentrations of resistin were analyzed in 45 type 2 diabetic subjects and 34 nondiabetic subjects. Subcutaneous human adipocytes were incubated in vitro with insulin, RSG, and insulin in combination with RSG to examine effects on resistin secretion. Serum resistin was increased by approximately 20% in type 2 diabetic subjects compared with nondiabetic subjects (P = 0.004) correlating with C-reactive protein. No other parameters, including adiposity and fasting insulin levels, correlated with serum resistin in this cohort. However, in vitro, insulin stimulated resistin protein secretion in a concentration-dependent manner in adipocytes [control, 1215 +/- 87 pg/ml (mean +/- SEM); 1 nM insulin, 1414.0 +/- 89 pg/ml; 1 microM insulin, 1797 +/- 107 pg/ml (P < 0.001)]. RSG (10 nM) reduced the insulin-mediated rise in resistin protein secretion (1 nM insulin plus RSG, 971 +/- 35 pg/ml; insulin, 1 microM insulin plus RSG, 1019 +/- 28 pg/ml; P < 0.01 vs. insulin alone). Glucose uptake was reduced after treatment with 10 ng/ml recombinant resistin and higher concentrations (P < 0.05). Our in vitro studies demonstrated a small, but significant, reduction in glucose uptake with human recombinant resistin in differentiated preadipocytes. In human abdominal sc adipocytes, RSG blocks the insulin-mediated release of resistin secretion in vitro. In conclusion, elevated serum resistin in human diabetes reflects the subclinical inflammation prevalent in type 2 diabetes. Our in vitro studies suggest a modest effect of resistin in reducing glucose uptake, and suppression of resistin expression may contribute to the insulin-sensitizing and glucose-lowering actions of the thiazolidinediones.
The purpose of this study was to examine the source of adipokines released by the visceral and sc adipose tissues of obese humans. Human adipose tissue incubated in primary culture for 48 h released more prostaglandin E(2), IL-8, and IL-6 than adiponectin, whereas the release of plasminogen activator inhibitor 1 and hepatocyte growth factor was less than that of adiponectin but greater than that of leptin. IL-10 and TNFalpha were released in amounts less than those of leptin, whereas vascular endothelial growth factor and IL1-beta were released in much lower amounts. The accumulation of adipokines was also examined in the three fractions (adipose tissue matrix, isolated stromovascular cells, and adipocytes) obtained by collagenase digestion of adipose tissue. Over 90% of the adipokine release by adipose tissue, except for adiponectin and leptin, could be attributed to nonfat cells. Visceral adipose tissue released greater amounts of vascular endothelial growth factor, IL-6, and plasminogen activator inhibitor 1 compared with abdominal sc tissue. The greatly enhanced total release of TNFalpha, IL-8, and IL-10 by adipose tissue from individuals with a body mass index of 45 compared with 32 was due to nonfat cells. Furthermore, most of the adipokine release by the nonfat cells of adipose tissue was due to cells retained in the tissue matrix after collagenase digestion.
We investigated the functions of adiponectin, an adipocyte-specific secretory protein and a new member of the family of soluble defense collagens, in hematopoiesis and immune responses. Adiponectin suppressed colony formation from colony-forming units (CFU)—granulocyte-macrophage, CFU-macrophage, and CFU-granulocyte, whereas it had no effect on that of burst-forming units—erythroid or mixed erythroid-myeloid CFU. In addition, adiponectin inhibited proliferation of 4 of 9 myeloid cell lines but did not suppress proliferation of erythroid or lymphoid cell lines except for one cell line. These results suggest that adiponectin predominantly inhibits proliferation of myelomonocytic lineage cells. At least one mechanism of the growth inhibition is induction of apoptosis because treatment of acute myelomonocytic leukemia lines with adiponectin induced the appearance of subdiploid peaks and oligonucleosomal DNA fragmentation. Aside from inhibiting growth of myelomonocytic progenitors, adiponectin suppressed mature macrophage functions. Treatment of cultured macrophages with adiponectin significantly inhibited their phagocytic activity and their lipopolysaccharide-induced production of tumor necrosis factor α. Suppression of phagocytosis by adiponectin is mediated by one of the complement C1q receptors, C1qRp, because this function was completely abrogated by the addition of an anti-C1qRp monoclonal antibody. These observations suggest that adiponectin is an important negative regulator in hematopoiesis and immune systems and raise the possibility that it may be involved in ending inflammatory responses through its inhibitory functions.
We investigated the functions of adiponectin, an adipocyte-specific secretory protein and a new member of the family of soluble defense collagens, in hematopoiesis and immune responses. Adiponectin suppressed colony formation from colony-forming units (CFU)—granulocyte-macrophage, CFU-macrophage, and CFU-granulocyte, whereas it had no effect on that of burst-forming units—erythroid or mixed erythroid-myeloid CFU. In addition, adiponectin inhibited proliferation of 4 of 9 myeloid cell lines but did not suppress proliferation of erythroid or lymphoid cell lines except for one cell line. These results suggest that adiponectin predominantly inhibits proliferation of myelomonocytic lineage cells. At least one mechanism of the growth inhibition is induction of apoptosis because treatment of acute myelomonocytic leukemia lines with adiponectin induced the appearance of subdiploid peaks and oligonucleosomal DNA fragmentation. Aside from inhibiting growth of myelomonocytic progenitors, adiponectin suppressed mature macrophage functions. Treatment of cultured macrophages with adiponectin significantly inhibited their phagocytic activity and their lipopolysaccharide-induced production of tumor necrosis factor α. Suppression of phagocytosis by adiponectin is mediated by one of the complement C1q receptors, C1qRp, because this function was completely abrogated by the addition of an anti-C1qRp monoclonal antibody. These observations suggest that adiponectin is an important negative regulator in hematopoiesis and immune systems and raise the possibility that it may be involved in ending inflammatory responses through its inhibitory functions.
Aims: The study was designed to survey the change of adiponectin levels before and after interferon-alpha (IFN-alpha) therapy in patients with chronic hepatitis B and C infections. Methods: Twenty-one biopsy-proved patients with chronic hepatitis B (10 cases) and hepatitis C (11 cases) were given IFN-alpha for a total of 24 weeks. Fasting plasma glucose, insulin and adiponectin levels were obtained before and 12 weeks after completion of IFN-alpha therapy. Insulin suppression test was conducted before and within 1 week after IFN-alpha therapy. Results: The change of adiponectin levels differed significantly between responders (eight cases) and non-responders (13 cases) to IFN-alpha treatment (-4.8 +/- 2.2 vs. 0.5 +/- 1.0 mu g/ml, P=0.03). After adjusting for age, gender and change in body mass index, the study found the change of adiponectin levels still significantly related to the response to IFN-alpha (P=0.04). When hepatitis B virus (HBV) and hepatitis C virus (HCV)-infected patients were separately analyzed, the adiponectin levels reported a trend to decrease in HCV responders (11.9 +/- 3.2 vs. 10.8 +/- 3.0 mu g/ml, P=0.02, n=4) and HBV responders (17.7 +/- 4.1 vs. 9.2 +/- 1.0 mu g/ml, P=0.10, n=4). In addition, a significant decrease of steady-state plasma glucose in insulin suppression test was noted in responders (13.6 +/- 1.8-11.7 +/- 1.2 mmol/l, P=0.03), but not in non-responders (12.3 +/- 1.1-11.0 +/- 1.0 mmol/l, P=0.20), after IFN-alpha therapy. Conclusions: IFN-alpha resulted in a decrease of serum adiponectin levels but an improvement of insulin resistance in responders to the treatment. The result contradicts previous concept of the relationship between insulin resistance and adiponectin levels. Whether and how the augmented immune response, which was supposed to result from the disappearance or the profound down-regulation of the virus or viral antigens in responders to IFN-alpha treatment, contributes to the lowering of adiponectin levels needs to be further investigated.
Obesity and insulin resistance accelerate the progression of fibrosis during chronic liver disease. Resistin antagonizes insulin action in rodents, but its role in humans is still controversial. The aims of this study were to investigate resistin expression in human liver and to evaluate whether resistin may affect the biology of activated human hepatic stellate cells (HSCs), key modulators of hepatic fibrogenesis. Resistin gene expression was low in normal human liver but was increased in conditions of severe fibrosis. Up-regulation of resistin during chronic liver damage was confirmed by immunohistochemistry. In a group of patients with alcoholic hepatitis, resistin expression correlated with inflammation and fibrosis, suggesting a possible action on HSCs. Exposure of cultured HSCs to recombinant resistin resulted in increased expression of the proinflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, through activation of nuclear factor (NF)-κB. Resistin induced a rapid increase in intracellular calcium concentration, mainly through calcium release from intracellular inositol triphosphate-sensitive pools. The intracellular calcium chelator BAPTA-AM blocked resistin-induced NF-κB activation and monocyte chemoattractant protein-1 expression. In conclusion, this study shows a role for resistin as an intrahepatic cytokine exerting proinflammatory actions in HSCs, via a Ca2+/NF-κB-dependent pathway and suggests involvement of this adipokine in the pathophysiology of liver fibrosis.
Background:
Adipocyte-derived hormones may represent a mechanism linking insulin resistance to cardiovascular disease. In the present study, we evaluated the direct effects of resistin, a novel adipocyte-derived hormone, on endothelial activation.
Methods and results:
Endothelial cells (ECs) were incubated with human recombinant resistin (10 to 100 ng/ML, 24 hours), and endothelin-1 (ET-1) release, ET-1 mRNA expression, and nitric oxide (NO) production were assessed. Transient transfection assays were used to evaluate the effects of resistin on transcription of human ET-1 gene promoter. Furthermore, the effects of resistin on AP-1-mutated ET-1 promoter were evaluated. The effects of resistin on expression of vascular cell adhesion molecule (VCAM-1) and monocyte chemoattractant chemokine (MCP-1) were studied in addition to CD40 receptor, CD40 ligand-induced MCP-1 expression, and tumor necrosis factor receptor-associated factor-3 (TRAF3), an inhibitor of CD40 signaling. Incubation of ECs with resistin resulted in an increase in ET-1 release and ET-1 mRNA expression, with no change in NO production. Whereas treatment with resistin resulted in an increase in ET-1 promoter activity, the AP-1-mutated promoter was inactive after resistin stimulation. Additionally, resistin-treated cells showed increased expression of VCAM-1 and MCP-1, with concomitant reductions in TRAF-3 expression. Resistin did not alter CD40 receptor expression; however, increased CD40 ligand induced MCP-1 production.
Conclusions:
The novel adipokine resistin exerts direct effects to promote EC activation by promoting ET-1 release, in part by inducing ET-1 promoter activity via the AP-1 site. Furthermore, resistin upregulates adhesion molecules and chemokines and downregulates TRAF-3, an inhibitor of CD40 ligand signaling. In this fashion, resistin may be mechanistically linked to cardiovascular disease in the metabolic syndrome.
ACRP30--adipocyte complement-related protein of 30 kDa or AdipoQ--is an abundant serum protein, secreted exclusively from fat cells, which is implicated in energy homeostasis and obesity [1,2]. ACRP30 is a close homologue of the complement protein C1q, which is involved in the recognition of microbial surfaces [3-5] and antibody-antigen complexes [6,7] in the classical pathway of complement. We have determined the crystal structure of a homotrimeric fragment from ACRP30 at 2.1 A resolution. The structure reveals an unexpected homology to the tumor necrosis factor (TNF) family. Identical folding topologies, key residue conservations, and similarity of trimer interfaces and intron positions firmly establish an evolutionary link between the TNF and C1q families. We suggest that TNFs--which control many aspects of inflammation, adaptive immunity, apoptosis and energy homeostasis--arose by divergence from a primordial recognition molecule of the innate immune system. The evolutionary connection between C1q-like proteins and TNFs illuminates the shared functions of these two important groups of proteins.
We isolated a novel adipose-specific gene, apM1, the transcript of which is the most abundant in the mRNA population from human adipose tissue. Northern blotting revealed that the human apM1 gene transcript is exclusively expressed in adipose tissue. The apM1 gene encodes a 244 amino acid open reading frame containing a putative signal sequence and G-X-Y repeats (66 amino acids) followed by a cluster of aromatic residues near the C terminus having high local similarity with collagens X and VIII and complement factor C1q. Thus, apM1 is likely to be a novel collagen-like secretory protein exclusively produced by adipose tissue.
The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor family of transcription factors, a large and diverse group of proteins that mediate ligand-dependent transcriptional activation and repression. Expression of PPAR-gamma is an early and pivotal event in the differentiation of adipocytes. Several agents that promote differentiation of fibroblast lines into adipocytes have been shown to be PPAR-gamma agonists, including several prostanoids, of which 15-deoxy-delta-prostaglandin J2 is the most potent, as well as members of a new class of oral antidiabetic agents, the thiazolidinediones, and a variety of non-steroidal anti-inflammatory drugs (NSAIDs). Here we show that PPAR-gamma agonists suppress monocyte elaboration of inflammatory cytokines at agonist concentrations similar to those found to be effective for the promotion of adipogenesis. Inhibition of cytokine production may help to explain the incremental therapeutic benefit of NSAIDs observed in the treatment of rheumatoid arthritis at plasma drug concentrations substantially higher than are required to inhibit prostaglandin G/H synthase (cyclooxygenase).
Members of the Hedgehog (Hh) and Wnt/Wingless (Wg) families of secreted proteins control many aspects of growth and patterning during animal development. Hh signal transduction leads to increased stability of a transcription factor, Cubitus interruptus (Ci), whereas Wg signal transduction causes increased stability of Armadillo (Arm/beta-catenin), a possible co-factor for the transcriptional regulator Lef1/TCF. Here we describe a new gene, slimb (for supernumerary limbs), which negatively regulates both of these signal transduction pathways. Loss of function of slimb results in a cell-autonomous accumulation of high levels of both Ci and Arm, and the ectopic expression of both Hh- and Wg- responsive genes. The slimb gene encodes a conserved F-box/WD40-repeat protein related to Cdc4p, a protein in budding yeast that targets cell-cycle regulators for degradation by the ubiquitin/proteasome pathway. We propose that Slimb protein normally targets Ci and Arm for processing or degradation by the ubiquitin/proteasome pathway, and that Hh and Wg regulate gene expression at least in part by inducing changes in Ci and Arm, which protect them from Slimb-mediated proteolysis.
Pediatric inflammatory bowel disease is often associated with growth failure and inadequate energy intake. Although several circulating cytokines are known to be elevated in inflammatory bowel disease, the mechanism for the related anorexia has not been described. Leptin is a newly recognized circulating protein that is an important regulator of appetite and energy metabolism; leptin levels are elevated in several animal models of inflammation. This study was conducted to determine whether serum leptin levels are elevated in young patients with inflammatory bowel disease.
One hundred twelve children and young adults with Crohn's disease or ulcerative colitis were studied prospectively. Forty-two patients with other gastrointestinal illnesses were used as control subjects. Height, weight, erythrocyte sedimentation rate, serum albumin concentration, and clinical information were collected prospectively, and leptin was measured by radioimmunoassay of stored serum.
No significant differences in leptin levels were found among disease groups or control subjects. Body mass index and gender were the only independent predictors of serum leptin in all groups examined. Disease activity varied inversely with serum leptin in patients with Crohn's disease, but these differences were explained entirely by variations in body mass index.
The determinants of serum leptin were the same in young patients with inflammatory bowel disease as in normal populations, indicating that alterations in leptin levels are unlikely to mediate the anorexia and growth failure associated with this disease.
1. Leptin inhibits food intake and is an important regulator of long-term energy balance. In rodents, plasma concentrations of leptin are increased by administration of interleukin-1 and tumour necrosis factor. Hyperleptinaemia may mediate the anorexia and weight loss which is observed in chronic infections and inflammatory conditions.
2. Plasma leptin and soluble tumour necrosis factor receptor (sTNF-r55) concentrations were measured in patients with inflammatory bowel disease and acquired immunodeficiency syndrome (AIDS), and healthy controls.
3. The patients with AIDS were severely wasted [% body fat 12 (9–16); median (interquartile range)] compared with those with inflammatory bowel disease (25.1 (19–31.5)] and control subjects [29.4 (23.6–37.8)]. Leptin concentrations were highly correlated with percentage body fat in controls (r = 0.74, P < 0.001) and patients with IBD (r = 0.73, P < 0.001) but not in the patients with AIDS (r = −0.024). Leptin concentrations were similar in the inflammatory bowel disease (4.8 (2.6–10.1) ng/ml] and control groups [8.0 (3.1–14.1) ng/ml] but were significantly lower (P < 0.05) in patients with AIDS (1.8 (1.5–2.3) ng/ml] after 23 patients were matched for sex and percentage body fat in patients with inflammatory bowel disease (2.4 (1.8–4.1) ng/ml]. Plasma concentrations of sTNF-r55 were higher in both the patients with inflammatory bowel disease [0.19 (0.16–0.23) ng/ml] and those with AIDS [4.8 (2.8–7.3) ng/ml] compared with controls [0.14 (0.09–0.16) ng/ml] but were not correlated with either percentage body fat or plasma leptin concentrations.
4. Hyperleptinaemia does not appear to mediate the anorexia and weight loss associated with inflammatory bowel disease and AIDS. In patients with AIDS with extreme wasting there was no relationship between body fat and leptin and this may be related to the rapid weight loss which occurs in these patients.
Nutritional deprivation suppresses immune function. The cloning of the obese gene and identification of its protein product leptin has provided fundamental insight into the hypothalamic regulation of body weight. Circulating levels of this adipocyte-derived hormone are proportional to fat mass but maybe lowered rapidly by fasting or increased by inflammatory mediators. The impaired T-cell immunity of mice now known to be defective in leptin (ob/ob) or its receptor (db/db), has never been explained. Impaired cell-mediated immunity and reduced levels of leptin are both features of low body weight in humans. Indeed, malnutrition predisposes to death from infectious diseases. We report here that leptin has a specific effect on T-lymphocyte responses, differentially regulating the proliferation of naive and memory T cells. Leptin increased Th1 and suppressed Th2 cytokine production. Administration of leptin to mice reversed the immunosuppressive effects of acute starvation. Our findings suggest a new role for leptin in linking nutritional status to cognate cellular immune function, and provide a molecular mechanism to account for the immune dysfunction observed in starvation.
We have previously demonstrated that genetically based leptin deficiency due to a missense leptin gene mutation in a highly consanguineous extended Turkish pedigree is associated with morbid obesity and hypogonadism. We have now performed detailed assessments of endocrine, sympathetic, and immune function. We have also identified a new adult female homozygous patient in this extended family who is severely obese and amenorrheic. In this family all wild-type and heterozgous individuals have normal body weight. Seven obese members of this family, whom we presume to have been leptin deficient, died during childhood. There are several findings that indicate potentially novel targets for leptin action in humans. Four homozygous patients (1 adult male, 2 adult females, and 1 child) have sympathetic system dysfunction, whereas all heterozygous subjects have normal sympathetic system function. Despite sympathetic system dysfunction and postural hypotension, 1 of 3 homozygous adult patients has impaired renin-aldosterone function. The patients also exhibit alterations in GH and PTH-calcium function, and 1 of them has decreased bone mineral density. Despite their obesity, these patients do not have risk factors for cardiovascular disease, such as hypertension, impairments in lipid metabolism, or hyperleptinemia [corrected]. These data support the hypothesis that the obese may have central, but not peripheral, resistance to the effects of leptin and that hyperleptinemia [corrected] may mediate the cardiovascular morbidity of the obese who are not leptin deficient. Furthermore, these data indicate that there may be several new targets for leptin action in human physiology. Such new targets may lead to novel pharmacological strategies for the use of leptin agonists and antagonists in the treatment of human disease. All 19 normal weight individuals in this family are alive, whereas 7 of 11 obese individuals died in childhood after infections. The odds ratio for mortality in the context of this obesity phenotype is 25.4, indicating that this mutation severely impairs key biological functions during childhood, negatively impacting on survival. We found that only the obese child in this family had thyroid function abnormalities. The oldest homozygous female patient started to menstruate, albeit with a luteal phase defect, 7 months ago, after a delay of over 20 yr, whereas the younger adult subjects are still hypogonadic. Thus, we conclude that due to their long life span, humans who survive the negative effects of leptin deficiency during childhood can, in contrast to ob/ob mice, over decades compensate some of the effects of leptin deficiency on immunity and endocrine function through mechanisms that remain to be elucidated.
Small synthetic molecules called growth-hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through GHS-R, a G-protein-coupled receptor for which the ligand is unknown. Recent cloning of GHS-R strongly suggests that an endogenous ligand for the receptor does exist and that there is a mechanism for regulating GH release that is distinct from its regulation by hypothalamic growth-hormone-releasing hormone (GHRH). We now report the purification and identification in rat stomach of an endogenous ligand specific for GHS-R. The purified ligand is a peptide of 28 amino acids, in which the serine 3 residue is n-octanoylated. The acylated peptide specifically releases GH both in vivo and in vitro, and O-n-octanoylation at serine 3 is essential for the activity. We designate the GH-releasing peptide 'ghrelin' (ghre is the Proto-Indo-European root of the word 'grow'). Human ghrelin is homologous to rat ghrelin apart from two amino acids. The occurrence of ghrelin in both rat and human indicates that GH release from the pituitary may be regulated not only by hypothalamic GHRH, but also by ghrelin.
Besides its actions on the regulation of appetite, leptin has also been implicated in regulating reproductive and immune functions. Because leptin-deficient mice are more susceptible to lipopolysaccharide- and tumor necrosis factor-alpha-induced shock, which is associated with lower levels of interleukin 1 receptor antagonist (IL-1Ra), we investigated whether leptin is a direct regulator of IL-1Ra in human monocytes. In human moncytic cells, leptin was capable of inducing a 6- to 10-fold increase in secreted IL-1Ra in a time- and dose-dependent manner. Moreover, leptin induced the messenger RNA for IL-1Ra within 8 h and specifically activated the promoter for this gene. However, leptin had no effect on the expression or secretion of IL-1 in THP-1 cells. This effect of leptin on monocytic cells requires the presence of the functional leptin receptor OB-Rb, which we have shown to be present in human monocytes by RT-PCR and by measuring the activation of the Jak/STAT pathway. In summary, we have demonstrated that leptin is capable of inducing the expression and secretion of IL-1Ra by human monocytes, an effect that is potentially mediated through the presence of functional leptin receptors on these cells. These findings suggest that leptin may have immunomodulatory functions in vivo.
We examined GH and GH receptor expression in human leukemic cell lines and leukocytes of normal subjects to elucidate the cell types expressing GH and GH receptor, the individual variations of their expressions, their correlation and the relationships with serum IgG and IGF-I concentrations. In addition, the expression of GH secretagogue receptor, which enhances GH secretion from the anterior pituitary by synthetic GH secretagogues and that of its endogenous ligand, ghrelin, were also examined in these immune cells. GH expression in human leukemic cell lines was observed mainly in B cell lines at both the mRNA and protein level [3.8 +/- 0.2 pg/10(6) cells in Raji and 19.9 +/- 3.3 pg/10(6) cells in Daudi vs. negligible in T cell lines (Jurkat and Hut-78) and in myeloid cell lines (K-562 and HL-60)]. B cells in normal subjects were also found to be the major immune cells expressing GH mRNA, with significant individual variation. GH receptor mRNA expression was detectable in all human leukemic cell lines, although the expression level varied widely among the cell lines and was weaker than that in the liver. On the other hand, GH receptor mRNA expression was mainly found in B cells, with marked individual variation in normal subjects. There was a positive correlation between the mRNA expressions of GH and GH receptor in B cells of normal subjects (r = 0.89; P < 0.001). Single cell RT-PCR revealed that some B cells expressed both GH and GH receptor transcripts, and others expressed only GH. GH/GH receptor expression levels in B cells did not show any correlation with serum IgG and IGF-I levels in normal subjects. Expression of GH secretagogue receptor and ghrelin was detectable in all immune cells regardless of the maturity and cell types with great individual variations. In summary, GH secreted from B cells may act locally on their own receptors, and their variable expressions may be related to individual immune functions. Widespread distribution of ghrelin and GH secretagogue receptor in human immune cells may indicate unknown biological functions other than enhancing GH secretion in the immune system.
Resistin, a novel signalling molecule isolated in mice has been suggested to be the putative hormone thought to link obesity with type 2 diabetes. The aim of this study was to examine resistin protein expression in human adipose tissue depots and resistin secretion in isolated adipose cells, to characterize resistin expression in human adipose tissue. Both resistin mRNA and protein expression were analysed from human adipose tissue (n = 5 adipose tissue samples: abdominal subcutaneous (Sc) n = 19, abdominal omental adipose tissue (Om) n = 10, thigh n = 9, breast n = 7). Resistin protein expression levels were similar in both the abdominal Sc and Om adipose tissue depots, and expression in abdominal fat depots were increased compared with thigh (p < 0.001) and breast tissue depots (p < 0.001). These findings were consistent with the mRNA expression studies. Resistin was secreted from both pre-adipocytes and adipocytes cells. Thus, resistin resides within isolated adipose cells and is expressed and secreted in human adipose tissue. In conclusion, this study confirms the expression of resistin in human adipose tissue and increased expression in abdominal fat, this suggests a potential role in linking central obesity to type 2 diabetes and/or cardiovascular disease.
Leptin is an adipocyte-secreted hormone that centrally regulates weight control via targeting the leptin receptor in the central nervous system. Recently, the leptin receptor has also been detected in peripheral systems including immune tissues, suggesting that leptin may play an important role in the regulation of immune function. It has been shown that leptin modulates functions of T lymphocytes, B lymphocytes, and monocytes/macrophage. However, the effect of leptin on NK cells remains unknown. In the present paper, we observed that percentage of NK cells and total amount of NK cells in the liver, spleen, lung, and peripheral blood were declined in leptin receptor deficient mice (db/db B6 mice), indicating that NK cell development was vigorously influenced by leptin receptor deficiency. Both basal and poly I:C-stimulated NK cell activation (CD69 surface marker expression) were retarded in db/db mice. In addition, leptin treatment increased the basal or synergistically enhanced IL-15- and poly I:C-induced specific lysis of splenocytes in normal littermates but not in db/db mice. Taken together, these findings suggest that leptin plays an important role in NK cell development and activation.
Resistin is a cysteine-rich protein postulated to be a molecular link between obesity and type 2 diabetes. The aim of this study was to investigate the role of PPAR gamma in the regulation of resistin expression in human primary macrophages. Fluorescent real-time PCR (Taqman) analysis of resistin expression across a range of human tissues showed that resistin is highly expressed in bone marrow compared to other tissues. Taqman analysis and Western blotting showed that rosiglitazone decreased resistin expression at both the mRNA and protein levels in human primary monocyte-derived macrophages in vitro. Resistin expression was reduced by up to 80% after exposure to 100 nM rosiglitazone for 96 h. Bioinformatics analysis of the genomic sequence upstream of the resistin coding sequence identified several putative PPAR response elements of which one was shown to bind PPAR gamma using electrophoretic mobility shift assays. Our data support a direct role for PPAR gamma in the regulation of resistin expression.
Resistin, also known as Fizz3 or ADSF, is a protein found in murine adipose tissue and inflammatory lung exudates. The present studies found that resistin was released by explants of human adipose tissue but the release was quite variable ranging from 3 to 158 ng/g over 48 h. The release of resistin was 250% greater by explants of omental than by explants of human subcutaneous abdominal adipose tissue. Resistin release by adipocytes was negligible as compared to that by the non-fat cells of adipose tissue. Leptin formation by adipocytes was 8-fold greater than its formation by the non-fat cells, while the formation of PAI-1 by adipocytes was 38% of that by the non-fat cells. The conversion of glucose to lactate as well as the formation of PGE(2) and IL-8 was approximately 15% of that by the non-fat cells. In contrast the release of IL-6 and IL-1beta by adipocytes was 4-7% of that by the non-fat cells while the formation of resistin and IL-10 by adipocytes was 2% of that by non-fat cells. The release of adiponectin by explants ranged from 1000 to 5000 ng/g over 48 h but did not correlate with that of resistin. The present data suggest that resistin release by explants of human adipose tissue in primary culture is largely derived from the non-fat cells present in the explants.
Leptin regulates energy homeostasis and participates in the regulation of the hypothalamic-pituitary-adrenal axis. Although hyperleptinemia is described in experimental colitis, its role in the pathophysiology of enterotoxin-mediated diarrhea and inflammation remains unclear. We examined the role of leptin in the inflammatory diarrhea induced by toxin A from Clostridium difficile, the causative agent of antibiotic-related colitis.
Toxin A (10 microg) or buffer were administered in ileal loops of leptin-deficient (ob/ob), leptin-resistant (db/db), or wild-type mice and enterotoxic responses were measured.
In toxin A-treated wild-type mice, circulating leptin and corticosterone levels were increased compared with buffer-injected animals. Toxin A also stimulated increased mucosal expression of the Ob-Rb at the messenger RNA (mRNA) and protein level. Ob/ob and db/db mice were partially protected against toxin A-induced intestinal secretion and inflammation, and this effect was reversed by leptin administration in ob/ob, but not db/db, mice. Basal- and toxin A-stimulated plasma corticosterone levels in ob/ob and db/db mice were higher compared with toxin A-treated wild-type mice. To assess whether the effect of leptin in intestinal inflammation is mediated by corticosteroids we performed adrenalectomy experiments in db/db and wild-type mice. Our results suggested that the diminished intestinal response to toxin A in db/db mice was related only in part to increased levels of corticosteroids.
Leptin plays an important role in regulating the severity of enterotoxin-mediated intestinal secretion and inflammation by activating both corticosteroid-dependent and -independent mechanisms.
Adiponectin is a 29-kDa adipocyte protein that has been linked to the insulin resistance of obesity and lipodystrophy. To better understand the regulation of adiponectin expression, we measured plasma adiponectin and adipose tissue adiponectin mRNA levels in nondiabetic subjects with varying degrees of obesity and insulin resistance. Plasma adiponectin and adiponectin mRNA levels were highly correlated with each other (r = 0.80, P < 0.001), and obese subjects expressed significantly lower levels of adiponectin. However, a significant sex difference in adiponectin expression was observed, especially in relatively lean subjects. When men and women with a BMI <30 kg/m(2) were compared, women had a twofold higher percent body fat, yet their plasma adiponectin levels were 65% higher (8.6 +/- 1.1 and 14.2 +/- 1.6 micro g/ml in men and women, respectively; P < 0.02). Plasma adiponectin had a strong association with insulin sensitivity index (S(I)) (r = 0.67, P < 0.0001, n = 51) that was not affected by sex, but no relation with insulin secretion. To separate the effects of obesity (BMI) from S(I), subjects who were discordant for S(I) were matched for BMI, age, and sex. Using this approach, insulin-sensitive subjects demonstrated a twofold higher plasma level of adiponectin (5.6 +/- 0.6 and 11.2 +/- 1.1 micro g/ml in insulin-resistant and insulin-sensitive subjects, respectively; P < 0.0005). Adiponectin expression was not related to plasma levels of leptin or interleukin-6. However, there was a significant inverse correlation between plasma adiponectin and tumor necrosis factor (TNF)-alpha mRNA expression (r = -0.47, P < 0.005), and subjects with the highest levels of adiponectin mRNA expression secreted the lowest levels of TNF-alpha from their adipose tissue in vitro. Thus, adiponectin expression from adipose tissue is higher in lean subjects and women, and is associated with higher degrees of insulin sensitivity and lower TNF-alpha expression.
The peptide hormone ghrelin is known to be present within stomach and, to a lesser extent, elsewhere in gut. Although reports suggest that gastric function may be modulated by ghrelin acting via the vagus nerve, the gastrointestinal distribution and functions of its receptor, the growth hormone secretagogue receptor (GHS-R), are not clear and may show signs of species-dependency. This study sought to determine the cellular localisation and distribution of GHS-R-immunoreactivity (-Ir) using immunofluorescent histochemistry and explore the function of ghrelin in both human and rat isolated gastric and/or colonic circular muscle preparations in which nerve-mediated responses were evoked by electrical field stimulation. The expression of GHS-R-Ir differed to a greater extent between species than between gut regions of the same species. Both the human and rat gastric and colonic preparations (n=3 each) expressed GHS-R-Ir within neuronal cell bodies and fibres, cells associated with gastric glands and putative entero-endocrine and/or mast cells. Smooth muscle cells and epithelia were devoid of GHS-R-Ir and only rat preparations expressed GHS-R-Ir on nerve fibres associated with the muscle layers. GHS-R-Ir was fully competed in all cases in pre-adsorption studies and antiserum specificity was confirmed using a cell line transiently expressing the rat GHS-R. In rat isolated forestomach circular muscle, ghrelin 0.1-10 microM had no effect on smooth muscle tension but concentration-dependently facilitated the amplitude of contractions evoked by excitatory nerve stimulation (n=4-7; P<0.05 for each concentration versus vehicle; n=18). When examined under similar conditions, in both rat distal colon (n=4-6, P>0.05 each) and human ascending (n=3) and sigmoid (n=1) colon, these concentrations of ghrelin were without effect (P>0.05 each). The data suggest that ghrelin has the potential to profoundly affect gastrointestinal functions in both species and at least one of these functions is to exert a gastric prokinetic activity. Moreover, we suggest that this activity of ghrelin is mediated via the enteric nervous system, in addition to known vagus nerve-dependent mechanisms.
Resistin is a recently discovered polypeptide that induces insulin resistance in rodents. While in rodents resistin is predominantly expressed in adipocytes, in humans peripheral blood mononuclear cells (PBMC) seem to a be a major source of resistin. In the present study, we show that in human PBMC resistin mRNA expression-determined by fluorescence-based real-time polymerase chain reaction-is strongly increased by the proinflammatory cytokines interleukin (IL)-1, IL-6, tumor necrosis factor alpha (TNF-alpha), and also by lipopolysaccharides (LPS), respectively, while no effect was found by interferon-gamma (IFN-gamma) or leptin. Our results suggest that in humans resistin may be a link in the well-known association between inflammation and insulin resistance.
The mechanisms underlying the cardiac activities of synthetic growth hormone secretagogues (GHS) are still unclear. The natural ligand of the GHS receptors, i.e. ghrelin, classically binds the GHS receptor and exerts endocrine actions in acylated forms only; its cardiovascular actions still need to be investigated further. In order to clarify these aspects, we studied the effects of either the synthetic peptidyl GHS hexarelin (1 microM), or the natural ghrelin (50 nM) and the endogenous ghrelin derivatives des-Gln14-ghrelin (1-100 nM) and des-octanoyl ghrelin (50 nM), on the tension developed by guinea pig papillary muscle and on L-type Ca2+ current (ICa) of isolated ventricular cells. The binding of these molecules to ventricular cell membrane homogenates was also studied. We observed that all peptides reduced the tension developed at low frequencies (60-120 beats/min) in a dose-dependent manner. No alteration in cardiac contractility was induced by des-Gln14-ghrelin or des-octanoylated ghrelin when the endocardial endothelium had been removed or after cyclooxygenase blockade. Pretreatment with tyramine (2 microM) had no effect on the inotropic response induced by des-Gln(14)-ghrelin. No significant effect on I(Ca) of isolated ventricular cells was observed in the presence of des-Gln14-ghrelin (100 nM). The order of potency on the tension of papillary muscle was: des-octanoyl ghrelin > ghrelin = des-Gln14-ghrelin > hexarelin. This gradient of potency was consistent with the binding experiments performed on ventricular membranes where either acylated or unacylated ghrelin forms, and hexarelin, recognized a common high-affinity binding site. In conclusion, ghrelin, des-Gln14-ghrelin and des-octanoyl ghrelin, show similar negative inotropic effect on papillary muscle; as des-octanoyl ghrelin is peculiarly devoid of any GH-releasing activity, the cardiotropic action of these molecules is independent of GH release. The binding studies and the experiments performed both on the isolated cells and on papillary muscle after endothelium removal or cyclooxygenase blockade indicate that the cardiotropic action of natural and synthetic ghrelin analogues reflects the interaction with a novel GHS receptor (peculiarly common for ghrelin and des-octanoyl ghrelin), leading to release of cyclooxygenase metabolites from endothelial cells, as indicated by direct measurement of prostacyclin metabolite 6-keto-PGF(1alpha).
