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Obesity, Metabolic Syndrome, and Musculoskeletal Disease: Common Inflammatory Pathways Suggest a Central Role for Loss of Muscle Integrity
Abstract and Figures
Inflammation can arise in response to a variety of stimuli, including infectious agents, tissue injury, autoimmune diseases, and obesity. Some of these responses are acute and resolve, while others become chronic and exert a sustained impact on the host, systemically, or locally. Obesity is now recognized as a chronic low-grade, systemic inflammatory state that predisposes to other chronic conditions including metabolic syndrome (MetS). Although obesity has received considerable attention regarding its pathophysiological link to chronic cardiovascular conditions and type 2 diabetes, the musculoskeletal (MSK) complications (i.e., muscle, bone, tendon, and joints) that result from obesity-associated metabolic disturbances are less frequently interrogated. As musculoskeletal diseases can lead to the worsening of MetS, this underscores the imminent need to understand the cause and effect relations between the two, and the convergence between inflammatory pathways that contribute to MSK damage. Muscle mass is a key predictor of longevity in older adults, and obesity-induced sarcopenia is a significant risk factor for adverse health outcomes. Muscle is highly plastic, undergoes regular remodeling, and is responsible for the majority of total body glucose utilization, which when impaired leads to insulin resistance. Furthermore, impaired muscle integrity, defined as persistent muscle loss, intramuscular lipid accumulation, or connective tissue deposition, is a hallmark of metabolic dysfunction. In fact, many common inflammatory pathways have been implicated in the pathogenesis of the interrelated tissues of the musculoskeletal system (e.g., tendinopathy, osteoporosis, and osteoarthritis). Despite these similarities, these diseases are rarely evaluated in a comprehensive manner. The aim of this review is to summarize the common pathways that lead to musculoskeletal damage and disease that result from and contribute to MetS. We propose the overarching hypothesis that there is a central role for muscle damage with chronic exposure to an obesity-inducing diet. The inflammatory consequence of diet and muscle dysregulation can result in dysregulated tissue repair and an imbalance toward negative adaptation, resulting in regulatory failure and other musculoskeletal tissue damage. The commonalities support the conclusion that musculoskeletal pathology with MetS should be evaluated in a comprehensive and integrated manner to understand risk for other MSK-related conditions. Implications for conservative management strategies to regulate MetS are discussed, as are future research opportunities.
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... However, these explanations do not match the development of OA in non-weightbearing joints in overweight adults, indicating that obesity contributes to OA development [3,4]. Nowadays, it is accepted that the rise in the prevalence of metabolic syndrome (MetS) is accompanied by a global increase in the prevalence of musculoskeletal diseases and disorders, such as OA [5]. As a consequence, OA is currently divided into multiple subgroups dependent on the risk factors involved, such as metabolic syndrome-associated OA, post-traumatic OA, and age-associated OA. ...
... Obesity, diabetes, dyslipidemia, and hypertension are linked to OA development [4]. The chronic low grade systemic inflammation state as well as the release of adipokines seem to be key factors in the development of OA derived from obesity [3,5,6], where an important contribution from the microbiota dysbiosis induced by diet may be also responsible for the development of this OA subgroup [3,4,7]. A structural degradation occurs in the cartilage as a consequence of low-grade inflammation and also because of the possible mechanical stress over the joint. ...
... Diverse studies have demonstrated that abdominal obesity is the most frequent component of the MetS. Obesity favours the growth of adipose tissue by increasing adipokines expression, the increase in serum glucose levels and the amount of serum low density lipoproteins (LDL) particles [5]. As a consequence, it promotes oxidative stress in the tissues and a chronic systemic inflammation, provoking a metabolic imbalance between organs and tissues [5,16]. ...
The relation between obesity and osteoarthritis (OA) development has been traditionally explained as consequence of the excessive joint effort derived of overweight. However, in the last two decades a metabolic OA has been suggested through diverse molecular mechanism implying metabolic syndrome, although more investigation must be conducted to elucidate it. Metabolic syndrome is responsible of the release of diverse inflammatory cytokines, specially the increased adipokine in obesity, causing a chronic low-grade inflammatory status that alters the joint homeostasis. In this scenario, the microbiota dysbiosis contribute by worsening the low-grade chronic inflammation or causing metabolic disorders mediated by endotoxemia generated by an increased lipopolysaccharides intake. This results in joint inflammation and cartilage degradation, which contributes to the development of OA. Also, the insulin resistance provoked by type 2 Diabetes contributes to the OA development. When intake patterns are considered, some coincidences can be pointed between the food patterns associated to the metabolic syndrome and the food patterns associated to OA development. Therefore, these coincidences support the idea of a molecular mechanism of the OA development caused by the molecular mechanism generated under the metabolic syndrome status. This review points the relation between metabolic syndrome and OA, showing the connected molecular mechanisms between both pathologies as well as the shared dietary patterns that promote or prevent both pathologies.
... On the other hand, reductions in physical activity and increases in energy intake, both linked with aging, consistently lead to the multiplication of fat cells, along with the recruitment of immunological cells known as macrophages. These cells release pro-inflammatory degrading signaling molecules termed adipokines produced by adipose tissue and found in osteoarthritis that may foster a state of reluctance to exercise due to pain and limited cardiovascular capacity as well as reduced muscle strength and functional impairment [30][31][32][33][34][35][36]. ...
... Ray In the meantime, Pedroso et al. [28] found people with knee osteoarthritis to exhibit a higher intramuscular fat fraction than healthy controls, thus they may experience excess disability. In addition, Karlsson et al. [29] note women and men with idiopathic knee osteoarthritis may have a specific body type wherein a higher body mass induces a greater joint load, and a proportionally lower muscle mass degrades the efficiency of any joint-protective ability, and thus this group might be specifically targeted to avert joint damage as well as any chronic and sustained inflammatory impact on the host, systemically, or locally, as well as impaired muscle integrity, and possible metabolic dysfunction [32,33]. Furthermore, certain cytokines, released by both skeletal muscle and adipose tissue and that exhibit a bioactive effect; and that are called adipo-myokines may modulate some, if not all, the molecular events that prevail in osteoarthritis. ...
EXAMINES HOW EXCESS MUSCLE ADIPOSE TISSUE CAN HAVE WIDE REACHING JOINT AND SYSTEMIC ADVERSE OSTEOARTHRITIS ASSOCIATED IMPACTS
... SM is predominantly responsible for postural stability, mobility, thermogenesis [13,14], and blood glucose (BG) homeostasis [15], and SM metabolism is essential for energy and glucose homeostasis. Furthermore, a compromised SM metabolism is associated with metabolic diseases such as type 2 diabetes (T2D) [16], obesity [17], and metabolic syndrome [18]. SM is largely responsible for glucose uptake and utilization in response to insulin and also maintains BG levels during fasting or exercise [19]. ...
Skeletal muscle (SM) plays a vital role in energy and glucose metabolism by regulating insulin sensitivity, glucose uptake, and blood glucose homeostasis. Impaired SM metabolism is strongly linked to several diseases, particularly type 2 diabetes (T2D). Insulin resistance in SM may result from the impaired activities of insulin receptor tyrosine kinase, insulin receptor substrate 1, phosphoinositide 3-kinase, and AKT pathways. This review briefly discusses SM myogenesis and the critical roles that SM plays in insulin resistance and T2D. The pharmacological targets of T2D which are associated with SM metabolism, such as DPP4, PTB1B, SGLT, PPARγ, and GLP-1R, and their potential modulators/inhibitors, especially natural compounds, are discussed in detail. This review highlights the significance of SM in metabolic disorders and the therapeutic potential of natural compounds in targeting SM-associated T2D targets. It may provide novel insights for the future development of anti-diabetic drug therapies. We believe that scientists working on T2D therapies will benefit from this review by enhancing their knowledge and updating their understanding of the subject.
... The NFκB signaling pathway can be activated by H 2 O 2 at different sites [77]. The activation of the NFκB signaling pathway is involved in musculoskeletal diseases including tendon diseases [78]. The MAPK pathway is a representative stress-responsive signaling pathway that induces cellular responses to divergent environmental stimuli [79]. ...
Background
Tendon injuries have a high incidence and limited treatment options. Stem cell transplantation is essential for several medical conditions like tendon injuries. However, high local concentrations of reactive oxygen species (ROS) inhibit the activity of transplanted stem cells and hinder tendon repair. Cerium oxide nanoparticles (CeONPs) have emerged as antioxidant agents with reproducible reducibility.
Results
In this study, we synthesized polyethylene glycol-packed CeONPs (PEG-CeONPs), which were loaded into the human umbilical cord mesenchymal stem cells (hUCMSCs) to counteract oxidative damage. H2O2 treatment was performed to evaluate the ROS scavenging ability of PEG-CeONPs in hUCMSCs. A rat model of patellar tendon defect was established to assess the effect of PEG-CeONPs-carrying hUCMSCs in vivo. The results showed that PEG-CeONPs exhibited excellent antioxidant activity both inside and outside the hUCMSCs. PEG-CeONPs protect hUCMSCs from senescence and apoptosis under excessive oxidative stress. Transplantation of hUCMSCs loaded with PEG-CeONPs reduced ROS levels in the tendon injury area and facilitated tendon healing. Mechanistically, NFκB activator tumor necrosis factor α and MAPK activator dehydrocrenatine, reversed the therapeutic effect of PEG-CeONPs in hUCMSCs, indicating that PEG-CeONPs act by inhibiting the NFκB and MAPK signaling pathways.
Conclusions
The carriage of the metal antioxidant oxidase PEG-CeONPs maintained the ability of hUCMSCs in the injured area, reduced the ROS levels in the microenvironment, and facilitated tendon regeneration. The data presented herein provide a novel therapeutic strategy for tendon healing and new insights into the use of stem cells for disease treatment.
Graphical Abstract
... Patients with MetS are more likely to be obese which could contribute to operative time. Collins et al. describe many potential pathways in which chronic, low-level inflammation spurred by obesity could contribute to poor bone and tendon quality, and therefore create additional challenge in fixation [18]. For our study, no insight on the quality of bone for fixation or whether these patients had inherently more complex injuries is available. ...
Background Studies demonstrate that metabolic syndrome (MetS) negatively impacts surgical outcomes. This study sought to identify how metabolic syndrome affects outcomes after open reduction and internal fixation (ORIF) of traumatic pilon fractures. Methods Patients who underwent ORIF for pilon fractures from 2012 to 2019 were identified in the American College of Surgeons National Surgical Quality Improvement Program database. Patients with MetS were compared to non-MetS patients for rates of adverse events, prolonged stay, readmission, discharge location, and operative time in the 30-day postoperative period. All statistical analyses were conducted using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). Paired student t-tests were used to assess continuous variables. Pearson's Chi-square and odds ratios were used for categorical variables. Results A total of 1,915 patients met this study's inclusion criteria, and 127 MetS patients were identified in the cohort. The MetS cohort was older (62.7 vs 49.5 years old, p-value <0.01), with a greater proportion of female patients (59.1% vs 50.2%, p=0.054). MetS patients experienced significantly higher rates of infectious complications (7.9% vs 3.9% OR 2.75 (CI 1.36-5.53), p=0.008), major adverse events (11% vs 4.3%, OR 2.79 (CI 1.53-5.09) p=0.002), and readmissions. MetS patients also had longer lengths of stay (7 days vs 3.8 days, p-value<0.001), and were more likely to be discharged to a non-home location (51.2% vs 19.5%, p-value<0.01, OR 4.32 (CI=3.0-6.24) p<0.001). Conclusion Patients with MetS have an increased risk of 30-day major complications, infection, readmissions, discharge to a non-home location, and prolonged operative time, and therefore warrant additional consideration for perioperative monitoring.
... There are many reasons for musculoskeletal aging such as alterations in body composition, inflammation and hormonal imbalance. Inflammatory molecules directly and indirectly affect musculoskeletal metabolism and endocrine system (30). Inflammaging is defined as age-related chronic inflammation and it is caused by the lifetime exposure to antigenic agents including clinical and subclinical infections (31). ...
Falls are a threat to the health of older adults and can reduce their ability to remain independent. Furthermore, fall is known as one of the geriatric syndromes and is more common in older people and about 20 to 40 percent of older people have reported a history of falling per year. It should be noted that fall or fear of falling causes immobility in the elderly and immobility is linked with various non-communicable diseases, geriatric syndromes development, and mortality in the long term. As a result, finding a cost-effective, safe, and proper approach to prevent, control, and even treat of falls is absolutely crucial. Regarding the exercise benefits in all ages especially in the elderly, we supposed that various types of exercise such as aerobic, balance, and resistance training with different intensities have variant advantages in these subjects. Therefore, in this review study, we investigated the charter of different types of exercise in preventing and controlling fall based on recent evidence, providing involved mechanisms, as well as the effects of exercises on fall-related risk factors.
... Recently, metabolic diseases were found to be vital contributors in osteoarthritis development (Collins et al., 2018;Misra et al., 2019;Mohajer et al., 2021). Metabolic syndrome is a cluster of conditions including high blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol levels (Furuta et al., 2023;Kassi et al., 2011). ...
High-fat diet induces bone marrow inflammation and osteoarthritis phenotype in knee joint, but the underlying mechanisms is unknown. Here, we report that high-fat diet induces aberrant bone formation and cartilage degeneration in knee joint. Mechanistically, a high-fat diet increases the number of macrophages and the secretion of prostaglandins in subchondral bone, promoting bone formation. Metformin treatment is able to decrease the number of macrophages and also the level of prostaglandins induced by high-fat diet in subchondral bone. Importantly, metformin rescues aberrant bone formation and cartilage lesions by decreasing the number of osteoprogenitors and type-H vessels, which also results in relief of osteoarthritis pain response. Thus, we demonstrate prostaglandins secreted by macrophages may be a key reason for high-fat diet induced aberrant bone formation and metformin is a promising therapy for high-fat diet induced osteoarthritis.
... In particular, a high concentration of new edges between the musculoskeletal and endocrine/metabolic disease categories is observed. This behavior is corroborated by prior research indicating associations between musculoskeletal degradation and the onset of metabolic disorders 28 . On the other hand, disease categories such as neoplasms and sense organs continue to remain relatively disconnected to other groupings, confirming conclusions drawn regarding cross-phenotype associations across disease categories in previous studies 4,8 .These differences across disease categories are due in part to the types of diseases that are genetically associated with the clinical measurements for which we had data to use. ...
Many diseases exhibit complex multimorbidities with one another. An intuitive way to model the connections between phenotypes is with a disease-disease network (DDN), where nodes represent diseases and edges represent associations, such as shared single-nucleotide polymorphisms (SNPs), between pairs of diseases. To gain further genetic understanding of molecular contributors to disease associations, we propose a novel version of the shared-SNP DDN (ssDDN), denoted as ssDDN+, which includes connections between diseases derived from genetic correlations with endophenotypes. We hypothesize that a ssDDN+ can provide complementary information to the disease connections in a ssDDN, yielding insight into the role of clinical laboratory measurements in disease interactions. Using PheWAS summary statistics from the UK Biobank, we constructed a ssDDN+ revealing hundreds of genetic correlations between disease phenotypes and quantitative traits. Our augmented network uncovers genetic associations across different disease categories, connects relevant cardiometabolic diseases, and highlights specific biomarkers that are associated with cross-phenotype associations. Out of the 31 clinical measurements under consideration, HDL-C connects the greatest number of diseases and is strongly associated with both type 2 diabetes and diabetic retinopathy. Triglycerides, another blood lipid with known genetics causes in non-mendelian diseases, also adds a substantial number of edges to the ssDDN. Our study can facilitate future network-based investigations of cross-phenotype associations involving pleiotropy and genetic heterogeneity, potentially uncovering sources of missing heritability in multimorbidities.
... La pérdida de masa muscular o sarcopenia se relaciona con la falta de movilidad y la ganancia de peso en estos pacientes. 14,15 A nivel gastrohepático, la obesidad ha propiciado aumento en los casos de esteatosis hepática no alcohólica, la cual se caracteriza por infiltración de grasa en el hígado. Los pacientes con sobrepeso y obesidad tienen también otras enfermedades gástricas, como enfermedad por reflujo gastroesofágico, esofagitis y sus complicaciones, enfermedad ácido-péptica, síndrome de intestino irritable y estreñimiento, debido especialmente a los hábitos alimenticios y al aumento de la presión intraabdominal. ...
El sobrepeso y la obesidad son condiciones patológicas multifactoriales que impactan directamente en el desarrollo de otras entidades metabólicas crónicas como diabetes mellitus tipo 2, hipertensión arterial sistémica y síndrome metabólico, así como con enfermedad hepática, distintos tipos de cáncer, problemas socioemocionales, entre otros. En este contexto se puede considerar que el binomio sobrepeso-obesidad es detonante de la mayoría de los padecimientos observados y tratados en el primer nivel de atención; por tal motivo, es fundamental que médicos familiares y de primer contacto conozcan el impacto que tiene dicho binomio en el desarrollo y agudización de múltiples enfermedades, con el propósito de establecer mecanismos integrales de acción que atenúen los efectos deletéreos ocasionados por incrementos en el índice de masa corporal. Fisiopatología La grasa corporal que se almacena en los seres humanos y otros mamíferos pudo haber sido una ventaja adaptativa durante periodos prolongados de inanición. Actualmente, el consumo excesivo de alimentos acompañado de poca actividad física promueve la acumulación de grasa corporal en el tejido adiposo, lo que eventualmente resulta en aumento de peso y obesidad.
Introduction and hypothesis:
The literature is scarce regarding the effects of comorbidities, clinical parameters, and lifestyle as risk factors for pelvic organ prolapse (POP). This study was performed to systematically review the literature related to body mass index (BMI), waist circumference, diabetes mellitus (DM), hypertension (HT), dyslipidemia, chronic constipation, smoking, chronic cough, occupation, and striae and varicose veins as determinants for POP.
Methods:
Search terms in accordance with Medical Subject Headings were used in PubMed, Embase, LILACS, and the Cochrane Library. Clinical comparative studies between women with and without POP and containing demographic and/or clinical raw data related to lifestyle and/or comorbidities were included. The ROBINS-I (risk of bias in non-randomized studies of interventions) instrument was used. Fixed-effects and random-effects models were used for homogeneous and heterogeneous studies, respectively.
Results:
Forty-three studies were included in the meta-analysis. BMI < 25 kg/m2 was found to be a protective factor for POP [OR 0.71 (0.51, 0.99); p = 0.04], and BMI > 30 kg/m2 was a risk factor for POP [OR 1.44 (1.37, 1.52); p < 0.00001]. Waist circumference (≥ 88 cm) was reported as a risk factor for POP [OR 1.80 (1.37, 2.38); p < 0.00001], along with HT [OR 1.18 (1.09, 1.27); p = 0.04], constipation [OR 1.77 (1.23, 2.54); p < 0.00001], occupation [OR 1.86 (1.21, 2.86); p < 0.00001], persistent cough [OR 1.52 (1.18, 1.94); p < 0.0001]), and varicose veins [OR 2.01 (1.50, 2.70); p = 0.12].
Conclusions:
BMI < 25 kg/m2 is protective while BMI > 30 kg/m2 is a risk factor for POP. Large waist circumference, dyslipidemia, HT, constipation, occupation, persistent cough, and varicose veins are also determinants for POP.
Objectives:
Metabolic syndrome and low-grade systemic inflammation are associated with knee osteoarthritis (OA), but the relationships between these factors and OA in other synovial joints are unclear. The aim of this study was to determine if a high-fat/high-sucrose (HFS) diet results in OA-like joint damage in the shoulders, knees, and hips of rats after induction of obesity, and to identify potential joint-specific risks for OA-like changes.
Methods:
A total of 16 male Sprague-Dawley rats were allocated to either the diet-induced obesity group (DIO, 40% fat, 45% sucrose, n = 9) or a chow control diet (n = 7) for 12 weeks. At sacrifice, histological assessments of the shoulder, hip, and knee joints were performed. Serum inflammatory mediators and body composition were also evaluated. The total Mankin score for each animal was assessed by adding together the individual Modified Mankin scores across all three joints. Linear regression modelling was conducted to evaluate predictive relationships between serum mediators and total joint damage.
Results:
The HFS diet, in the absence of trauma, resulted in increased joint damage in the shoulder and knee joints of rats. Hip joint damage, however, was not significantly affected by DIO, consistent with findings in human studies. The total Mankin score was increased in DIO animals compared with the chow group, and was associated with percentage of body fat. Positive significant predictive relationships for total Mankin score were found between body fat and two serum mediators (interleukin 1 alpha (IL-1α) and vascular endothelial growth factor (VEGF)).
Conclusion:
Systemic inflammatory alterations from DIO in this model system may result in a higher risk for development of knee, shoulder, and multi-joint damage with a HFS diet.Cite this article: K. H. Collins, D. A. Hart, R. A. Seerattan, R. A. Reimer, W. Herzog. High-fat/high-sucrose diet-induced obesity results in joint-specific development of osteoarthritis-like degeneration in a rat model. Bone Joint Res 2018;7:274-281. DOI: 10.1302/2046-3758.74.BJR-2017-0201.R2.
Background & aims:
It might be possible to manipulate the intestinal microbiota with prebiotics or other agents to prevent or treat obesity. However, little is known about the ability of prebiotics to specifically modify gut microbiota in children with overweight/obesity or reduce body weight. We performed a randomized controlled trial to study the effects of prebiotics on body composition, markers of inflammation, bile acids in fecal samples, and composition of the intestinal microbiota in children with overweight or obesity.
Methods:
We performed a single-center, double-blind, placebo-controlled trial of 2 separate cohorts (March 2014 and August 2014) at the University of Calgary in Canada. Participants included children, 7-12 years old, with overweight or obesity (>85th percentile of body mass index) but otherwise healthy. Participants were randomly assigned to groups given either oligofructose-enriched inulin (OI; 8 g/day; n=22) or maltodextrin placebo (isocaloric dose, controls; n=20) once daily for 16 weeks. Fat mass and lean mass were measured using dual-energy-x-ray absorptiometry. Height, weight, and waist circumference were measured at baseline and every 4 weeks thereafter. Blood samples were collected at baseline and 16 weeks, and analyzed for lipids, cytokines, lipopolysaccharide, and insulin. Fecal samples were collected at baseline and 16 weeks; bile acids were profiled using high-performance liquid chromatography and the composition of the microbiota was analyzed by 16S rRNA sequencing and quantitative polymerase chain reaction. The primary outcome was change in percent body fat from baseline to 16 weeks.
Results:
After 16 weeks, children who consumed OI had significant decreases in body weight z-score (decrease of 3.1%), percent body fat (decrease of 2.4%), and percent trunk fat (decrease of 3.8%) compared with children given placebo (increase of 0.5%, increase of 0.05%, and decrease of 0.3%, respectively). Children who consumed OI also had a significant reduction in level of interleukin 6 from baseline (decrease of 15%) compared with the placebo group (increase of 25%). There was a significant decrease in serum triglycerides (decrease of 19%) in the OI group. Quantitative polymerase chain reaction showed a significant increase in Bifidobacterium spp. in the OI group compared with controls. 16S rRNA sequencing revealed significant increases in species of the genus Bifidobacterium and decreases in Bacteroides vulgatus within the group who consumed OI. In fecal samples, levels of primary bile acids increased in the placebo group but not in the OI group over the 16-week study period.
Conclusions:
In a placebo-controlled, randomized trial, we found a prebiotic (OI) to selectively alter the intestinal microbiota and significantly reduce body weight z-score, percent body fat, percent trunk fat, and serum level of interleukin 6 in children with overweight or obesity (Clinicaltrials.gov no: NCT02125955).
The effects of obesity on different musculoskeletal tissues are not well understood. The glycolytic quadriceps muscles are compromised with obesity, but due to its high oxidative capacity, the soleus muscle may be protected against obesity-induced muscle damage. To determine the time–course relationship between a high-fat/high-sucrose (HFS) metabolic challenge and soleus muscle integrity, defined as intramuscular fat invasion, fibrosis and molecular alterations over six time points. Male Sprague-Dawley rats were fed a HFS diet (n = 64) and killed at serial short-term (3 days, 1 week, 2 weeks, 4 weeks) and long-term (12 weeks, 28 weeks) time points. Chow-fed controls (n = 21) were killed at 4, 12, and 28 weeks. At sacrifice, animals were weighed, body composition was calculated (DXA), and soleus muscles were harvested and flash-frozen. Cytokine and adipokine mRNA levels for soleus muscles were assessed, using RT-qPCR. Histological assessment of muscle fibrosis and intra-muscular fat was conducted, CD68 + cell number was determined using immunohistochemistry, and fiber typing was assessed using myosin heavy chain protein analysis. HFS animals demonstrated significant increases in body fat by 1 week, and this increase in body fat was sustained through 28 weeks on the HFS diet. Short-term time-point soleus muscles demonstrated up-regulated mRNA levels for inflammation, atrophy, and oxidative stress molecules. However, intramuscular fat, fibrosis, and CD68 + cell number were similar to their respective control group at all time points evaluated. Therefore, the oxidative capacity of the soleus may be protective against diet-induced alterations to muscle integrity. Increasing oxidative capacity of muscles using aero-bic exercise may be a beneficial strategy for mitigating obesity-induced muscle damage, and its consequences.
Osteoarthritis (OA) is a chronic disease that degrades the joints and is often associated with increasing age and obesity. The two most common sites of OA in adults are the knee and hip joints. Increased mechanical stress on the joint from obesity can cause the articular cartilage to degrade and release damage-associated molecular patterns (DAMPs). These DAMPs are involved in various molecular pathways that interact with nuclear factor-kappa B and result in the transcription of inflammatory cytokines and activation of matrix metalloproteinases that progressively destroy cartilage. This review focuses on the interactions and contribution to the pathogenesis and progression of OA through the DAMPs: high-mobility group box 1 (HMGB-1), the receptor for advanced glycation end-products (RAGE), the alarmin proteins S100A8 and S100A9, and heparan sulfate. HMGB-1 is released from damaged or necrotic cells and interacts with toll-like receptors (TLRs) and RAGE to induce inflammatory signals, as well as behave as an inflammatory cytokine to activate innate immune cells. RAGE interacts with HMGB-1, advanced glycation end-products, and innate immune cells to increase local inflammation. The alarmin proteins are released following cell damage and interact through TLRs to increase local inflammation and cartilage degradation. Heparan sulfate has been shown to facilitate the binding of HMGB-1 to RAGE and could play a role in the progression of OA. Targeting these DAMPs may be the potential therapeutic strategies for the treatment of OA.
Leptin, an adipocyte-derived cytokine associated with bone metabolism, is believed to play a critical role in the pathogenesis of heterotopic ossification (HO). The effect and underlying action mechanism of leptin were investigated on osteogenic differentiation of tendon-derived stem cells (TDSCs) in vitro and the HO formation in rat tendons. Isolated rat TDSCs were treated with various concentrations of leptin in the presence or absence of mTORC1 signaling specific inhibitor rapamycin in vitro. A rat model with Achilles tenotomy was employed to evaluate the effect of leptin on HO formation together with or without rapamycin treatment. In vitro studies with TDSCs showed that leptin increased the expression of osteogenic biomarkers (alkaline phosphatase, runt-related transcription factor 2, osterix, osteocalcin) and enhanced mineralization of TDSCs via activating the mTORC1 signal pathway (as indicated by phosphorylation of p70 ribosomal S6 kinase 1 and p70 ribosomal S6). However, mTORC1 signaling blockade with rapamycin treatment suppressed leptin-induced osteogenic differentiation and mineralization. In vivo studies showed that leptin promoted HO formation in the Achilles tendon after tenotomy, and rapamycin treatment blocked leptin-induced HO formation. In conclusion, leptin can promote TDSC osteogenic differentiation and heterotopic bone formation via mTORC1 signaling in both in vitro and in vivo models, which provides a new potential therapeutic target for HO prevention. This article is protected by copyright. All rights reserved.
Dietary fat strongly affects human health by modulating gut microbiota composition and low-grade systemic inflammation. High-fat diets have been implicated in reduced gut microbiota richness, increased Firmicutes to Bacteroidetes ratio, and several changes at family, genus and species levels. Saturated (SFA), monounsaturated (MUFA), polyunsaturated (PUFA) and conjugated linolenic fatty acids share important pathways of immune system activation/inhibition with gut microbes, modulating obesogenic and proinflammatory profiles. Mechanisms that link dietary fat, gut microbiota and obesity are mediated by increased intestinal permeability, systemic endotoxemia, and the activity of the endocannabinoid system. Although the probiotic therapy could be a complementary strategy to improve gut microbiota composition, it did not show permanent effects to treat fat-induced dysbiosis. Based upon evidence to date, we believe that high-fat diets and SFA consumption should be avoided, and MUFA and omega-3 PUFA intake should be encouraged in order to regulate gut microbiota and inflammation, promoting body weight/fat control.
Progranulin is a cysteine-rich secreted protein with diverse pleiotropic actions and participates in several processes, such as inflammation or tumorigenesis. Progranulin was first identified as a growth factor and, recently, it was characterised as an adipokine implicated in obesity, insulin resistance and rheumatic disease. At a central level, progranulin acts as a neurotropic and neuroprotective factor and protects from neural degeneration. In this review, we summarise the most recent research advances concerning the potential role of progranulin as a therapeutic target and biomarker in cancer, neurodegenerative and inflammatory diseases.
Objective:
Macrophages are believed to play a critical role in the inflammation associated with the development of osteoarthritis (OA) in obesity. The objective of the study was to investigate whether short-term, systemic depletion of macrophages would mitigate OA following injury in obese mice.
Methods:
CSF-1R-GFP(+) Macrophage Fas-Induced Apoptosis (MaFIA) transgenic mice that allow conditional depletion of macrophages were placed on a high-fat diet and underwent surgery to induce knee OA. A small molecule (AP20187) was administrated to deplete macrophages in MaFIA mice. The effect of macrophage depletion on acute joint inflammation, OA severity, and arthritic bone changes were evaluated using histology and microCT. Immunohistochemistry was used to identify various immune cells. Serum and synovial fluid cytokines were also measured.
Results:
Macrophage-depleted mice had significantly fewer M1 and M2 macrophages in the surgical operated-joints relative to controls and exhibited decreased osteophyte formation immediately following depletion. Surprisingly, macrophage depletion did not attenuate OA with obesity; instead, it induced systemic inflammation and led to a massive infiltration of CD3(+) T cells and particularly neutrophils, but not B cells, into the injured joints. Macrophage-depleted mice also demonstrated markedly increased pro-inflammatory cytokines including granulocyte-colony stimulating factor (G-CSF), IL-1β, IL-6, IL-8, and TNF-α in both serum and joint synovial fluid, although animals showed trends for decreased serum insulin and leptin levels after depletion.
Conclusion:
Our findings indicate that macrophages are vital in modulating the homeostasis of immune cells in obesity and suggest that more targeted approaches of different macrophage subtypes may be necessary to mitigate inflammation and OA with obesity. This article is protected by copyright. All rights reserved.
Background/objectives:
Obesity can affect muscle phenotypes, and may thereby constrain movement and energy expenditure. Weight loss is a common and intuitive intervention for obesity, but it is not known whether the effects of obesity on muscle function are reversible by weight loss. Here we tested whether obesity-induced changes in muscle metabolic and contractile phenotypes are reversible by weight loss.
Subjects/methods:
We used zebrafish (Danio rerio) in a factorial design to compare energy metabolism, locomotor capacity, muscle isometric force and work-loop power output, and myosin heavy chain composition between lean fish, diet-induced obese fish, and fish that were obese and then returned to lean body mass following diet restriction.
Results:
Obesity increased resting metabolic rates (P<0.001) and decreased maximal metabolic rates (P=0.030), but these changes were reversible by weight-loss, and were not associated with changes in muscle citrate synthase activity. In contrast, obesity-induced decreases in locomotor performance (P=0.0034), and isolated muscle isometric stress (P=0.01), work loop power output (P<0.001), and relaxation rates (P=0.012) were not reversed by weight loss. Similarly, obesity-induced decreases in concentrations of fast and slow myosin heavy chains, and a shift towards fast myosin heavy chains were not reversed by weight loss.
Conclusion:
Obesity-induced changes in locomotor performance and muscle contractile function were not reversible by weight loss. These results show that weight loss alone may not be a sufficient intervention.International Journal of Obesity accepted article preview online, 24 March 2017. doi:10.1038/ijo.2017.81.