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Liver-spleen axis, Insulin-like Growth Factor-(IGF)-I axis and fat mass in overweight/obese females

  • August 2011
  • Journal of Translational Medicine 9(1):136
DOI:10.1186/1479-5876-9-136
Authors:
Silvia Savastano at University of Naples Federico II
Silvia Savastano
Carolina Di Somma at University of Naples Federico II
Carolina Di Somma
Genoveffa Pizza at University of Naples Federico II
Genoveffa Pizza
Annalba De Rosa
Annalba De Rosa
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Abstract and Figures

Fat mass (FM) in overweight/obese subjects has a primary role in determining low-grade chronic inflammation and, in turn, insulin resistance (IR) and ectopic lipid storage within the liver. Obesity, aging, and FM influence the growth hormone/insulin-like growth factor (IGF)-I axis, and chronic inflammation might reduce IGF-I signaling. Altered IGF-I axis is frequently observed in patients with Hepatic steatosis (HS). We tested the hypothesis that FM, or spleen volume and C-reactive protein (CRP)--all indexes of chronic inflammation--could affect the IGF-I axis status in overweight/obese, independently of HS. The study population included 48 overweight/obese women (age 41 ± 13 years; BMI: 35.8 ± 5.8 kg/m2; range: 25.3-53.7), who underwent assessment of fasting plasma glucose and insulin, homeostasis model assessment of insulin resistance (HOMA), cholesterol and triglycerides, HDL-cholesterol, transaminases, high-sensitive CRP, uric acid, IGF-I, IGF binding protein (BP)-1, IGFBP-3, and IGF-I/IGFBP-3 ratio. Standard deviation score of IGF-I according to age (zSDS) were also calculated. FM was determined by bioelectrical impedance analysis. HS severity grading (score 0-4 according liver hyperechogenicity) and spleen longitudinal diameter (SLD) were evaluated by ultrasound. Metabolic syndrome (MS) and HS were present in 33% and 85% of subjects, respectively. MS prevalence was 43% in subjects with increased SLD. IGF-I values, but not IGF-I zSDS, and IGF-I/IGFBP-3 ratio were significantly lower, while FM%, FPI, HOMA, ALT, CRP, were significantly higher in patients with severe HS than in those with mild HS. IGF-I zSDS (r = -0.42, r = -0.54, respectively; p < 0.05), and IGFBP-1 (r = -0.38, r = -0.42, respectively; p < 0.05) correlated negatively with HS severity and FM%. IGF-I/IGFBP-3 ratio correlated negatively with CRP, HS severity, and SLD (r = -0.30, r = -0.33, r = -0.43, respectively; p < 0.05). At multivariate analysis the best determinants of IGF-I were FM% (β = -0.49; p = 0.001) and IGFBP-1 (β = -0.32; p = 0.05), while SLD was in the IGF-I/IGFBP-3 ratio (β = -0.43; p = 0.004). The present study suggests that lower IGF-I status in our study population is associated with higher FM, SLD, CRP and more severe HS.
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... Moreover, a spleen-liver axis has been defined to describe the crosstalk between spleen and liver (15)(16)(17). Spleen-derived cytokines including TGF-β1, IL-10, and TNF (18)(19)(20), chemokine like CCL2 (21), and factors involved in metabolic activities (16,22) have been shown to play essential roles in linking spleen and liver (23). Yet, little evidence is provided for splenocytes acting as mediate factors of the spleen-liver axis, although a few studies in liver diseases have demonstrated altered composition of hepatic immune cells upon splenectomy (6)(7)(8)(9)24). ...
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  • Sep 2022
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... Indeed, several reports have defined a significant connection between NAFLD and the GH/IGF-1 axis (4,19). Patients with NAFLD have reduced levels of IGF-1 (20), and IGF-1 deficiency can facilitate the development and advancement of NAFLD (21). In adolescents and adults with NAFLD patients, recombinant human growth hormone (rhGH) supplementation therapy has been shown to significantly improve hepatic steatosis and fibrosis (22,23). ...
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Article
Full-text available
  • Feb 2024
Context Although the role of insulin-like growth factor I (IGF-1) in nonalcoholic fatty liver disease (NAFLD) has garnered attention in recent years, few studies have examined both reduced and elevated levels of IGF-1. Objective The aim of this study was to examine the potential relationship between IGF-1 levels and the risk of new-onset NAFLD in patients with pituitary neuroendocrine tumors (PitNET). Methods We employed multivariable Cox regression models and two-piecewise regression models to assess the association between IGF-1 and new-onset NAFLD. Hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated to quantify this association. Furthermore, a dose-response correlation between lgIGF-1 and the development of NAFLD was plotted. Additionally, we also performed subgroup analysis and a series sensitivity analysis. Results A total of 3,291 PitNET patients were enrolled in the present study, and the median duration of follow-up was 65 months. Patients with either reduced or elevated levels of IGF-1 at baseline were found to be at a higher risk of NAFLD compared to PitNET patients with normal IGF-1(log-rank test, P < 0.001). In the adjusted Cox regression analysis model (model IV), compared with participants with normal IGF-1, the HRs of those with elevated and reduced IGF-1 were 2.33 (95% CI 1.75, 3.11) and 2.2 (95% CI 1.78, 2.7). Furthermore, in non-adjusted or adjusted models, our study revealed a U-shaped relationship between lgIGF-1 and the risk of NAFLD. Moreover, the results from subgroup and sensitivity analyses were consistent with the main results. Conclusions There was a U-shaped trend between IGF-1 and new-onset NAFLD in patients with PitNET. Further evaluation of our discoveries is warranted.
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... Firstly, many obesity-related factors, such as insulin resistance, glucose homeostasis, and chronic in ammation, affect the GH/IGF-1 axis, leading to GH resistance and reducing circulating IGF-1 levels [29][30][31][32] . Secondly, hyperinsulinemia combined with obesity may down-regulate the expression level of IGF-1 binding proteins (IGF-BPs) and inhibit circulating IGF-1 through negative feedback regulation 33 .In addition, Bann et al. 34 and Savastano al. 35 found that low IGF-1 is associated with high fat mass in people with obesity, suggesting that the distribution and content of adipose tissue in the body may also affect IGF-1 levels. In conclusion, further studies are needed to clarify the speci c mechanisms underlying the effects of obesity status on IGF-1. ...
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Preprint
Full-text available
  • Nov 2023
Objectives: Insulin-like growth factor1 (IGF-1) is a polypeptide hormone mainly secreted from the liver. The synthesis and secretion of IGF-1 are affected by various factors including unusual body weight. Nonetheless, the causal relationship between body mass index (BMI) and IGF-1 is still under debate from existing epidemiological studies, implying their complicated regulation pattern. Aiming to investigate their causal association, we conducted a large-scale linear and non-linear Mendelian randomization (MR) analysis in the UK Biobank (UKB) cohort with BMI as the exposure and IGF-1 as the outcome. Methods: After applying a series of exclusion criteria and covariate adjustment, a total of 244 991 participants from the UKB were eligible for analysis. The polygenic risk score (PRS) of BMI was constructed on 96 instrumental variables (IVs). The non-linear observational association between BMI and IGF-1 was examined by a restricted cubic spline test. Non-linear MR analysis was performed with the piecewise linear method and verified by doubly-ranked stratification and log-transformation methods. In addition to combined analysis, stratified analysis was performed by sex and age groups. A series of sensitivity analyses were performed to examine the robustness of the results. Results: Restricted cubic spline regression demonstrated an inverted U-shaped association between BMI and IGF-1 (P non-linear<0.001), which was also supported by MR analysis (Quadratic P-value: 4.93×10⁻⁶, Cochran Q P-value: 2.94×10⁻⁵). Specifically, genetically predicted BMI was significantly positively correlated with IGF-1 levels when BMI was less than 25kg/m², and genetically predicted BMI was significantly negatively correlated with IGF-1 levels when BMI exceeded around 28kg/m². Stratified analysis showed no difference against sex and different age groups. Sensitivity analyses gave similar results, demonstrating the robustness of the results. Conclusions: This study suggested a non-linear causal relationship between BMI and IGF-1 and this effect may not influenced by sex and age.
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... Another possible reason for the different results regarding the correlation between steatosis and IGF-1 levels may be the application of IGF-1 SDS in Sumida et al.'s study. Indeed, the relationship between IGF-1 and steatosis may become less evident when IGF-1 SDS is applied [24,43]. Similarly, Dichtel et al. found no significant association between mean serum IGF-1 levels and steatosis [11]. ...
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  • Feb 2023
Diabetic and obese patients have a high prevalence of non-alcoholic fatty liver disease (NAFLD). This condition groups a spectrum of conditions varying from simple steatosis to non-alcoholic steatohepatitis (NASH), with or without fibrosis. Multiple factors are involved in the development of NAFLD. However, details about its pathogenesis and factors that promote the progression to NASH are still missing. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) regulate metabolic, immune, and hepatic stellate cell functions. Increasing evidence suggests they may have roles in the progression from NAFLD to NASH. Following the PRISMA reporting guidelines, we conducted a systematic review to evaluate all clinical and experimental studies published in the literature correlating GH and IGF-1 to inflammation and fibrosis in NAFLD and NASH. Our results showed that GH and IGF-1 have a fundamental role in the pathogenesis of NASH, acting in slightly different ways to produce a synergic effect. Indeed, GH may mediate its protective effect in the pathogenesis of NASH by regulating lipogenesis pathways, while IGF-1 has the same effect by regulating cholesterol transport. Therefore, they could be used as therapeutic strategies in preventing NAFLD progression to NASH.
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... IGF-1 plays an important role in energy metabolism [69,70]. IGF-1 deficiency is associated with obesity [71] and hypertension [72]. This age-related condition can also occur in a younger population, i.e., gestational hypertension. ...
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Full-text available
  • Jan 2023
  • MOLECULES
Insulin-like growth factor-1 (IGF-1) function declines with age and is associated with brain ageing and the progression of age-related neurological conditions. The reversible binding of IGF-1 to IGF binding protein (IGFBP)-3 regulates the amount of bioavailable, functional IGF-1 in circulation. Cyclic glycine-proline (cGP), a metabolite from the binding site of IGF-1, retains its affinity for IGFBP-3 and competes against IGF-1 for IGFBP-3 binding. Thus, cGP and IGFBP-3 collectively regulate the bioavailability of IGF-1. The molar ratio of cGP/IGF-1 represents the amount of bioavailable and functional IGF-1 in circulation. The cGP/IGF-1 molar ratio is low in patients with age-related conditions, including hypertension, stroke, and neurological disorders with cognitive impairment. Stroke patients with a higher cGP/IGF-1 molar ratio have more favourable clinical outcomes. The elderly with more cGP have better memory retention. An increase in the cGP/IGF-1 molar ratio with age is associated with normal cognition, whereas a decrease in this ratio with age is associated with dementia in Parkinson disease. In addition, cGP administration reduces systolic blood pressure, improves memory, and aids in stroke recovery. These clinical and experimental observations demonstrate the role of cGP in regulating IGF-1 function and its potential clinical applications in age-related brain diseases as a plasma biomarker for—and an intervention to improve—IGF-1 function.
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... There was a lack of association between adiponectin and IGF-1 levels in patients with morbid obesity after weight loss induced by bariatric surgery 32 whereas in young women with non-diabetic obesity a positive association between IGF-1 and adiponectin was found. 33 In the latter study, a significant negative correlation between IGF-1 and CRP was observed indicating that inflammation may be causal for the positive association between IGF-1 and adiponectin because inflammation may impair the expression of both hormones [33][34][35] (for a review, see Kirk et al. 36 ). ...
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Full-text available
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Transcriptomic profiling of a multiethnic pediatric NAFLD cohort reveals genes and pathways associated with disease
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  • Mar 2022
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AKTIVITAS ANTIDISLIPIDEMIA EKSTRAK ETANOL HERBA PEGAGAN (Centella asiatica L. Urb) PADA TIKUS WISTAR JANTAN OBESITAS YANG DIINDUKSI PAKAN TINGGI LEMAK DAN KARBOHIDRAT
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Full-text available
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In vivo and in silico study of antioxidant and anti-inflammatory effects on liver-spleen axis of microencapsulated brewers’ spent grain peptides.
Article
  • May 2023
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Discriminating between body fat and fluid changes in the obese adult using bioimpedance vector analysis
Article
Full-text available
  • Feb 1998
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Article
Full-text available
  • Jan 2011
  • EUR RADIOL
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Article
Full-text available
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  • J Atherosclerosis Thromb
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Validity of Real Time Ultrasound in the Diagnosis of Hepatic Steatosis: A Prospective Study
Article
Full-text available
  • Sep 2009
Ultrasound is used to screen for hepatic steatosis, the most common liver disease in the United States. However, few studies have prospectively evaluated the accuracy of ultrasound to diagnose hepatic steatosis. Therefore, a double blinded prospective study was performed in consecutive patients undergoing liver biopsy to evaluate the accuracy of ultrasound to diagnose hepatic steatosis. Real time ultrasound was performed just prior to the biopsy by a single investigator masked to the clinical diagnosis. The liver biopsy was reviewed by a pathologist masked to the clinical indication or sonographic findings. Of 73 consecutive patients studied, macrovesicular steatosis of any severity on biopsy was found in 46 (63%) and micro vesicular fat found in 51 (69.9%). The overall impression of the sonographer for the presence of macrovesicular hepatic steatosis of any degree had a sensitivity of 60.9% and a specificity of 100%. The sensitivity increased to 100% and the specificity to 90% when there was > or =20% of fat. The zonular distribution of the fat did not alter the diagnostic accuracy of ultrasound. Ultrasound had a poor yield in the diagnosis of microvesicular fat with an overall sensitivity of 43% and a specificity of 73%. The combination of increased echogenicity and portal vein blurring on ultrasound had the greatest sensitivity in the diagnosis of hepatic steatosis. Real time ultrasound using a combination of sonographic findings has a high specificity but underestimates the prevalence of hepatic steatosis when there is<20% fat.
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Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III)
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Associations between plasma insulin-like growth factor-I and the markers of inflammation interleukin 6, C-reactive protein and YKL-40 in an elderly background population
Article
  • Jul 2010
  • INFLAMM RES
The objective of the present study was to test the hypothesis that circulating levels of insulin-like growth factor-I (IGF-I) are inversely associated with inflammatory processes in an elderly background population. We conducted a population-based study comprising 629 individuals, aged 50-89 years. Associations between plasma IGF-I versus interleukin 6 (IL-6) and the acute phase proteins high sensitive C-reactive protein (hsCRP) and YKL-40 were evaluated by linear regression analyses. Subsequently, the population was dichotomised at a CRP level of 3.0 mg/L and the associations were re-evaluated in the two subgroups. Adjusted for confounding variables, plasma IGF-I was inversely related to IL-6, hsCRP and YKL-40 (all P < 0.001). The strongest association was found for YKL-40 with a 34% reduction in YKL-40 per twofold increase in IGF-I. A significant inverse association between IGF-I and all markers of inflammation persisted in individuals with hsCRP below 3.0 mg/L whereas only YKL-40 was significantly associated with IGF-I in individuals with hsCRP above 3.0 mg/L. The data support the hypothesis of an inverse association between GH/IGF-I signalling and inflammation, and suggest that the relationship between the IGF-I and inflammation might be more predominant in healthy individuals with a low inflammatory activity.
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Validity of Bioelectrical Impedance Analysis to Estimate Body Composition Changes After Bariatric Surgery in Premenopausal Morbidly Women
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  • Oct 2009
  • OBES SURG
In obese patients, subtle variations of the hydration of soft tissues can propagate errors in bioelectrical impedance analysis (BIA) measures of body composition. Bioelectrical impedance vector analysis (BIVA) is a useful method to evaluate tissue hydration. Laparoscopic adjustable gastric banding (LAGB) is a purely restrictive bariatric surgical procedure resulting in lower fat-free mass (FFM) loss than other malabsorptive or mixed intervention. The aim of this study was to evaluate the 6- and 12-month changes in body composition in a homogeneous group of premenopausal morbidly obese women treated by LAGB by comparing the results of conventional BIA and BIVA with dual-energy X-ray absorptiometry (DXA) method. Forty-five consecutive morbidly obese patients (mean age, 35.3 ± 9.1 years; body mass index, 34.5–48.7 kg/m2) were prospectively evaluated at the Endocrinology Unit of the Department of Molecular and Clinical Endocrinology and Oncology. The LAGB device (Lap-Band™ System; Inamed Health, Santa Barbara, CA, USA) was inserted laparoscopically. Soft tissue hydration was evaluated by BIVA; fat mass (FM) and FFM were evaluated by BIA (BIA 101 RJL, Akern Bioresearch, Firenze, Italy) and by DXA (Hologic QDR 4500A S/N 45622; Hologic Inc., Bedford, MA, USA). Pre- and postoperative BIVA vectors indicated a normal hydration in all patients. Postoperatively, the excess of body weight loss was mainly due to a decrease in FM. The regression analysis of BIA and DXA methods at baseline and at the 6- and 12-month follow-up for FM r 2 values were 0.98, 0.94, and 0.99, respectively (p
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Obesity, growth hormone and weight loss
Article
  • Sep 2009
Growth hormone (GH) is the most important hormonal regulator of postnatal longitudinal growth in man. In adults GH is no longer needed for longitudinal growth. Adults with growth hormone deficiency (GHD) are characterised by perturbations in body composition, lipid metabolism, cardiovascular risk profile and bone mineral density. It is well established that adult GHD usually is accompanied by an increase in fat accumulation and GH replacement in adult patients with GHD results in reduction of fat mass and abdominal fat mass in particular. It is also recognized that obesity and abdominal obesity in particular results in a secondary reduction in GH secretion and subnormal insulin-like growth factor-I (IGF-I) levels. The recovery of the GH IGF-I axis after weight loss suggest an acquired defect, however, the pathophysiologic role of GH in obesity is yet to be fully understood. In clinical studies examining the efficacy of GH in obese subjects very little or no effect are observed with respect to weight loss, whereas GH seems to reduce total and abdominal fat mass in obese subjects. The observed reductions in abdominal fat mass are modest and similar to what can be achieved by diet or exercise interventions.
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