scholarly journals Branched-chain amino acid metabolism, insulin sensitivity and liver fat response to exercise training in sedentary dysglycaemic and normoglycaemic men

Diabetologia ◽  
2020 ◽  
Author(s):  
Sindre Lee ◽  
Hanne L. Gulseth ◽  
Torgrim M. Langleite ◽  
Frode Norheim ◽  
Thomas Olsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Plasma Concentration ◽  
Fat Mass ◽  
Liver Fat ◽  
Liver Fat Content ◽  
Mrna Sequencing ◽  
Branched Chain

Abstract Aims/hypothesis Obesity and insulin resistance may be associated with elevated plasma concentration of branched-chain amino acids (BCAAs) and impaired BCAA metabolism. However, it is unknown whether the insulin-sensitising effect of long-term exercise can be explained by concomitant change in BCAAs and their metabolism. Methods We included 26 sedentary overweight and normal-weight middle-aged men from the MyoGlu clinical trial, with or without dysglycaemia, for 12 weeks of supervised intensive exercise intervention, including two endurance and two resistance sessions weekly. Insulin sensitivity was measured as the glucose infusion rate (GIR) from a hyperinsulinaemic−euglycaemic clamp. In addition, maximum oxygen uptake, upper and lower body strength and adipose tissue depots (using MRI and spectroscopy) were measured, and subcutaneous white adipose tissue (ScWAT) and skeletal muscle (SkM) biopsies were harvested both before and after the 12 week intervention. In the present study we have measured plasma BCAAs and related metabolites using CG-MS/MS and HPLC-MS/MS, and performed global mRNA-sequencing pathway analysis on ScWAT and SkM. Results In MyoGlu, men with dysglycaemia displayed lower GIR, more fat mass and higher liver fat content than normoglycaemic men at baseline, and 12 weeks of exercise increased GIR, improved body composition and reduced liver fat content similarly for both groups. In our current study we observed higher plasma concentrations of BCAAs (14.4%, p = 0.01) and related metabolites, such as 3-hydroxyisobutyrate (19.4%, p = 0.034) in dysglycaemic vs normoglycaemic men at baseline. Baseline plasma BCAA levels correlated negatively to the change in GIR (ρ = −0.41, p = 0.037) and $$ \dot{V}{\mathrm{O}}_{2\max } $$ V ̇ O 2 max (ρ = −0.47, p = 0.015) after 12 weeks of exercise and positively to amounts of intraperitoneal fat (ρ = 0.40, p = 0.044) and liver fat (ρ = 0.58, p = 0.01). However, circulating BCAAs and related metabolites did not respond to 12 weeks of exercise, with the exception of isoleucine, which increased in normoglycaemic men (10 μmol/l, p = 0.01). Pathway analyses of mRNA-sequencing data implied reduced BCAA catabolism in both SkM and ScWAT in men with dysglycaemia compared with men with normoglycaemia at baseline. Gene expression levels related to BCAA metabolism correlated positively with GIR and markers of mitochondrial content in both SkM and ScWAT, and negatively with fat mass generally, and particularly with intraperitoneal fat mass. mRNA-sequencing pathway analysis also implied increased BCAA metabolism after 12 weeks of exercise in both groups and in both tissues, including enhanced expression of the gene encoding branched-chain α-ketoacid dehydrogenase (BCKDH) and reduced expression of the BCKDH phosphatase in both groups and tissues. Gene expression of SLC25A44, which encodes a mitochondrial BCAA transporter, was increased in SkM in both groups, and gene expression of BCKDK, which encodes BCKDH kinase, was reduced in ScWAT in dysglycaemic men. Mediation analyses indicated a pronounced effect of enhanced SkM (~53%, p = 0.022), and a moderate effect of enhanced ScWAT (~18%, p = 0.018) BCAA metabolism on improved insulin sensitivity after 12 weeks of exercise, based on mRNA sequencing. In comparison, plasma concentration of BCAAs did not mediate any effect in this regard. Conclusion/interpretation Plasma BCAA concentration was largely unresponsive to long-term exercise and unrelated to exercise-induced insulin sensitivity. On the other hand, the insulin-sensitising effect of long-term exercise in men may be explained by enhanced SkM and, to a lesser degree, also by enhanced ScWAT BCAA catabolism.

scholarly journals Metabolically healthy obesity: what's in a name?

2019 ◽  
Vol 110 (3) ◽  
pp. 533-539 ◽  
Author(s):  
Faidon Magkos
Keyword(s):  
Weight Loss ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Visceral Adipose Tissue ◽  
Liver Fat ◽  
Metabolically Healthy Obesity ◽  
Liver Fat Content ◽  
Metabolically Healthy ◽  
Visceral Adipose

ABSTRACT Metabolically healthy obesity refers to an obesity phenotype with no or little evidence of metabolic dysfunction. Lower liver fat content and visceral adipose tissue, greater insulin sensitivity and secretion, greater cardiorespiratory fitness, and a predominantly lower body (i.e., leg) fat deposition are key physiological traits of a metabolically healthy phenotype. About 35% of all subjects with obesity are metabolically healthy. These individuals have approximately half the risk of developing type 2 diabetes and cardiovascular disease compared with metabolically unhealthy subjects with obesity, but they still have a significantly greater risk (by 50–300%) compared with metabolically healthy lean subjects. Therefore, absence of metabolic risk factors in people with obesity should not be a contraindication for weight-loss treatment. Metabolically healthy obesity needs to be treated, and this need is reinforced by the fact that this phenotype is not stable over time, as ∼50% of these subjects will cease being metabolically healthy within ∼10 y. Intervening early is therefore important. Weight loss dose-dependently decreases visceral adipose tissue and liver fat content, and it improves multiorgan insulin sensitivity and β-cell function (i.e., it beneficially affects many of the physiological traits of a metabolically healthy phenotype); however, weight loss is very difficult to maintain. This typically results in disappointment among patients and hinders adherence, which is likely critical for the limited success of most weight-loss treatments in the long term. On the other hand, using ≥1 metabolic health targets in a non-weight-loss-centered treatment paradigm that includes prudent dietary changes and increased physical activity can serve as an appropriate first goal that can help motivate patients toward the long-term goals of obesity treatment.

Adipose tissue inflammation and liver fat in patients with highly active antiretroviral therapy-associated lipodystrophy

2008 ◽  
Vol 295 (1) ◽  
pp. E85-E91 ◽  
Author(s):  
Ksenia Sevastianova ◽  
Jussi Sutinen ◽  
Katja Kannisto ◽  
Anders Hamsten ◽  
Matti Ristola ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Liver Fat ◽  
Adipose Tissue Inflammation ◽  
Liver Fat Content ◽  
Abdominal Adipose Tissue ◽  
Highly Active ◽  
Subcutaneous Abdominal Adipose Tissue

In this cross-sectional study, we sought to determine whether gene expression of macrophage markers and inflammatory chemokines in lipoatrophic subcutaneous abdominal adipose tissue and liver fat content are increased and interrelated in human immunodeficiency virus (HIV)-1-positive, highly active antiretroviral therapy (HAART)-treated patients with lipodystrophy (HAART+LD+; n = 27) compared with those without (HAART+LD−; n = 13). The study groups were comparable with respect to age, gender, and body mass index. The HAART+LD+ group had twofold more intra-abdominal ( P = 0.01) and 1.5-fold less subcutaneous ( P = 0.091) fat than the HAART+LD− group. As we have reported previously, liver fat was 10-fold higher in the HAART+LD+ compared with the HAART+LD− group ( P = 0.00003). Inflammatory gene expression was increased in HAART-lipodystrophy: CD68 4.5-fold ( P = 0.000013), tumor necrosis factor (TNF)-α 2-fold ( P = 0.0094), chemokine (C-C motif) ligand (CCL) 2 2.5-fold ( P = 0.0024), CCL3 7-fold ( P = 0.0000017), integrin αM (ITGAM) 3-fold ( P = 0.00067), epidermal growth factor-like module containing, mucin-like, hormone receptor-like (EMR)1 2.5-fold ( P = 0.0038), and a disintegrin and metalloproteinase domain (ADAM)8 3.5-fold ( P = 0.00057) higher in the HAART+LD+ compared with the HAART+LD− group. mRNA concentration of CD68 ( r = 0.37, P = 0.019), ITGAM ( r = 0.35, P = 0.025), CCL2 ( r = 0.39, P = 0.012), and CCL3 ( r = 0.54, P = 0.0003) correlated with liver fat content. In conclusion, gene expression of markers of macrophage infiltration and adipose tissue inflammation is increased in lipoatrophic subcutaneous abdominal adipose tissue of patients with HAART-associated lipodystrophy compared with those without. CD68, ITGAM, CCL2, and CCL3 expression is significantly associated with accumulation of liver fat.

scholarly journals Elevated Circulating Glutamate Is Associated With Subclinical Atherosclerosis Independently of Established Risk Markers: A Cross-Sectional Study

2020 ◽  
Author(s):  
Angela Lehn-Stefan ◽  
Andreas Peter ◽  
Jürgen Machann ◽  
Fritz Schick ◽  
Elko Randrianarisoa ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Body Fat ◽  
Fat Mass ◽  
Visceral Fat ◽  
Fat Content ◽  
Liver Fat ◽  
Body Fat Mass ◽  
Elevated Plasma ◽  
Liver Fat Content ◽  
Increased Risk

Abstract Objective Elevated plasma glutamate levels are associated with an increased risk of cardiovascular disease (CVD). Because plasma glutamate levels are also strongly associated with visceral adiposity, nonalcoholic fatty liver disease, insulin resistance, and high circulating levels of branched-chain amino acids (BCAAs), it is unknown to what extent elevated circulating glutamate is an independent marker of an increased risk of atherosclerosis. Methods Plasma levels of glutamate and BCAAs were measured in 102 individuals who were precisely phenotyped for body fat mass and distribution (magnetic resonance [MR] tomography), liver fat content (1H-MR spectroscopy), insulin sensitivity (oral glucose tolerance test and hyperinsulinemic, euglycemic clamp [N = 57]), and carotid intima media thickness (cIMT). Results Plasma glutamate levels, adjusted for age, sex, body fat mass, and visceral fat mass, correlated positively with liver fat content and cIMT (all std β ≥ .22, all P ≤ .023) and negatively with insulin sensitivity (std β ≤ –.31, P ≤ .002). Glutamate levels also were associated with cIMT, independently of additional adjustment for liver fat content, insulin sensitivity and BCAAs levels (std β ≥ .24, P ≤ .02). Furthermore, an independent positive association of glutamate and interleukin-6 (IL-6) levels was observed (N = 50; std β = .39, P = .03). Although glutamate, adjusted for age, sex, body fat mass, and visceral fat mass, also correlated positively with cIMT in this subgroup (std β = .31, P = .02), after additional adjustment for the parameters liver fat content, insulin sensitivity, BCAAs, or IL-6 levels, adjustment for IL-6 most strongly attenuated this relationship (std β = .28, P = .05). Conclusions Elevated plasma glutamate levels are associated with increased cIMT, independently of established CVD risk factors, and this relationship may in part be explained by IL-6-associated subclinical inflammation.

scholarly journals LMO3 reprograms visceral adipocyte metabolism during obesity

2021 ◽  
Author(s):  
Gabriel Wagner ◽  
Anna Fenzl ◽  
Josefine Lindroos-Christensen ◽  
Elisa Einwallner ◽  
Julia Husa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Visceral Adipose Tissue ◽  
Tissue Expansion ◽  
Oxidative Capacity ◽  
Glut4 Translocation ◽  
Mitochondrial Oxidative Capacity ◽  
Visceral Adipose

Abstract Obesity and body fat distribution are important risk factors for the development of type 2 diabetes and metabolic syndrome. Evidence has accumulated that this risk is related to intrinsic differences in behavior of adipocytes in different fat depots. We recently identified LIM domain only 3 (LMO3) in human mature visceral adipocytes; however, its function in these cells is currently unknown. The aim of this study was to determine the potential involvement of LMO3-dependent pathways in the modulation of key functions of mature adipocytes during obesity. Based on a recently engineered hybrid rAAV serotype Rec2 shown to efficiently transduce both brown adipose tissue (BAT) and white adipose tissue (WAT), we delivered YFP or Lmo3 to epididymal WAT (eWAT) of C57Bl6/J mice on a high-fat diet (HFD). The effects of eWAT transduction on metabolic parameters were evaluated 10 weeks later. To further define the role of LMO3 in insulin-stimulated glucose uptake, insulin signaling, adipocyte bioenergetics, as well as endocrine function, experiments were conducted in 3T3-L1 adipocytes and newly differentiated human primary mature adipocytes, engineered for transient gain or loss of LMO3 expression, respectively. AAV transduction of eWAT results in strong and stable Lmo3 expression specifically in the adipocyte fraction over a course of 10 weeks with HFD feeding. LMO3 expression in eWAT significantly improved insulin sensitivity and healthy visceral adipose tissue expansion in diet-induced obesity, paralleled by increased serum adiponectin. In vitro, LMO3 expression in 3T3-L1 adipocytes increased PPARγ transcriptional activity, insulin-stimulated GLUT4 translocation and glucose uptake, as well as mitochondrial oxidative capacity in addition to fatty acid oxidation. Mechanistically, LMO3 induced the PPARγ coregulator Ncoa1, which was required for LMO3 to enhance glucose uptake and mitochondrial oxidative gene expression. In human mature adipocytes, LMO3 overexpression promoted, while silencing of LMO3 suppressed mitochondrial oxidative capacity. LMO3 expression in visceral adipose tissue regulates multiple genes that preserve adipose tissue functionality during obesity, such as glucose metabolism, insulin sensitivity, mitochondrial function, and adiponectin secretion. Together with increased PPARγ activity and Ncoa1 expression, these gene expression changes promote insulin-induced GLUT4 translocation, glucose uptake in addition to increased mitochondrial oxidative capacity, limiting HFD-induced adipose dysfunction. These data add LMO3 as a novel regulator improving visceral adipose tissue function during obesity. Key messages LMO3 increases beneficial visceral adipose tissue expansion and insulin sensitivity in vivo. LMO3 increases glucose uptake and oxidative mitochondrial activity in adipocytes. LMO3 increases nuclear coactivator 1 (Ncoa1). LMO3-enhanced glucose uptake and mitochondrial gene expression requires Ncoa1.

scholarly journals Liver Fat Content and Body Fat Distribution in Youths with Excess Adiposity

2018 ◽  
Vol 7 (12) ◽  
pp. 528 ◽  
Author(s):  
Robinson Ramírez-Vélez ◽  
Mikel Izquierdo ◽  
Jorge Correa-Bautista ◽  
María Correa-Rodríguez ◽  
Jacqueline Schmidt-RioValle ◽  
...  
Keyword(s):  
Body Fat ◽  
Fat Mass ◽  
Fat Distribution ◽  
Fat Content ◽  
Body Fat Distribution ◽  
Healthy Diet ◽  
Liver Fat ◽  
Liver Fat Content ◽  
Excess Adiposity ◽  
Distribution Parameters

This study had two main objectives: To examine the association between body fat distribution and non-alcoholic fatty liver disease (NAFLD) and liver fat content, and to determine whether the relationship between NAFLD and regional body fat distribution, with respect to liver fat content in youths with excess adiposity, is independent of cardiorespiratory fitness (CRF) and a healthy diet. Liver fat content (controlled attenuation parameter (CAP)), body fat distribution (body mass index (BMI) z-score, waist circumference, waist-to-height ratio, fat mass/height, body fat percentage, total fat mass, android-to-gynoid fat mass ratio, visceral adipose tissue (VAT), and lean mass index, determined by dual-energy X-ray absorptiometry (DXA)), CRF (20-m shuttle-run test), and healthy diet (adherence to the Mediterranean diet by KIDMED questionnaire) were measured in 126 adolescents (66% girls) aged between 11 and 17 years. Participants were assigned to two groups according to the presence or absence of hepatic steatosis (CAP values ≥225 dB/m or <225 dB/m of liver fat, respectively). Considering the similar total fat values for the two groups (>30% by DXA), youths with NAFLD had higher fat distribution parameters than those without NAFLD, regardless of sex, age, puberty stage, lean mass index, CRF, and healthy diet (p < 0.01). In the non-NAFLD group, the association between hepatic fat and fat distribution parameters presented a similar pattern, although the association was statistically insignificant after adjusting for a potential confounding variable (ps > 0.05), except for the case of VAT. Body fat distribution parameters were higher in youths with NAFLD compared to those without NAFLD. Additionally, body fat distribution showed a significant association with liver fat content as assessed by CAP in youths with NAFLD independent of CRF and adherence to the Mediterranean diet, supporting the notion that upper body fat distribution might play a pivotal role in the development of NAFLD in adolescents. These results may have implications for the clinical management of youths with excess adiposity given the high prevalence of NAFLD in children and young adults.

scholarly journals GH effect on enzyme activity of 11βHSD in abdominal obesity is dependent on treatment duration

2006 ◽  
Vol 154 (1) ◽  
pp. 69-74 ◽  
Author(s):  
Helga Á Sigurjónsdóttir ◽  
Josef Koranyi ◽  
Magnus Axelson ◽  
Bengt-Åke Bengtsson ◽  
Gudmundur Johannsson
Keyword(s):  
Insulin Sensitivity ◽  
Abdominal Obesity ◽  
Fat Mass ◽  
Visceral Fat ◽  
Controlled Trial ◽  
Metabolic Effects ◽  
Glucose Disposal ◽  
Gh Treatment ◽  
Double Blind

Objective: In the past years the interaction of GH and 11βhydroxysteroid dehydrogenase (11βHSD) in the pathogenesis of central obesity has been suggested. Design: We studied the effects of 9 months of GH treatment on 11βHSD activity and its relationship with body composition and insulin sensitivity in 30 men with abdominal obesity, aged 48–66 years, in a randomised, double-blind, placebo-controlled trial. Methods: Urinary steroid profile was used to estimate 11βHSD type 1 and 2 (11βHSD1 and 11βHSD2) activities. Abdominal s.c. and visceral adipose tissues were measured using computed tomography. Glucose disposal rate (GDR) obtained during a euglycaemic–hyperinsulinaemic glucose clamp was used to assess insulin sensitivity. Results: In the GH-treated group the 11βHSD1 activity decreased transiently after 6 weeks (P < 0.01) whereas 11βHSD2 increased after 9 months of treatment (P < 0.05). Between 6 weeks and 9 months, GDR increased and visceral fat mass decreased. Changes in 11βHSD1 correlated with changes in visceral fat mass between baseline and 6 weeks. There were no significant correlations between 11βHSD1 and 11βHSD 2 and changes in GDR. Discussion: The study demonstrates that short- and long-term GH treatment has different effects on 11βHSD1 and 11βHSD2 activity. Moreover, the data do not support that long-term metabolic effects of GH are mediated through its action on 11βHSD.

scholarly journals Adherence to a plant-based diet in relation to adipose tissue volumes and liver fat content

2020 ◽  
Vol 112 (2) ◽  
pp. 354-363
Author(s):  
Ilka Ratjen ◽  
Jakub Morze ◽  
Janna Enderle ◽  
Marcus Both ◽  
Jan Borggrefe ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Fat Distribution ◽  
Abdominal Fat ◽  
Fat Content ◽  
Liver Fat ◽  
Healthy Plant ◽  
Liver Fat Content ◽  
Subcutaneous Abdominal Adipose Tissue ◽  
Visceral Adipose

ABSTRACT Background Better adherence to plant-based diets has been linked to lower risk of metabolic diseases but the effect on abdominal fat distribution and liver fat content is unclear. Objectives We aimed to examine the association between different plant-based diet indices and measures of abdominal fat distribution and liver fat content. Methods In a population-based sample of 578 individuals from Northern Germany (57% male, median age 62 y), diet was assessed with a validated FFQ and an overall, a healthy, and an unhealthy plant-based diet index were derived. Participants underwent MRI to assess volumes of visceral and subcutaneous abdominal adipose tissue and liver signal intensity (LSI), a measure of liver fat content. Fatty liver disease (FLD) was defined as log LSI ≥3.0. Cross-sectional associations of the plant-based diet indices with visceral and subcutaneous abdominal fat volumes, LSI, and FLD were assessed in linear and logistic regression analyses. The most comprehensive model adjusted for age, sex, education, smoking, alcohol, physical activity, energy intake, diabetes, hyperlipidemia, and BMI. Results Higher overall and healthy plant-based diet indices both revealed statistically significant associations with lower visceral and subcutaneous abdominal adipose tissue volumes and with lower odds of FLD in multivariable-adjusted models without BMI. Upon additional adjustment for BMI, only the association of the healthy plant-based diet with visceral adipose tissue remained statistically significant (per 10-point higher healthy plant-based diet index, percentage change in visceral adipose tissue: −4.9%, 95% CI: −8.6%, −2.0%). None of the plant-based diet indices was associated with LSI. The unhealthy plant-based diet index was unrelated to any of the abdominal or liver fat parameters. Conclusions Adherence to healthy plant-based diets was associated with lower visceral adipose tissue. None of the other examined associations remained statistically significant after adjustment for BMI.

scholarly journals No Independent Association of Circulating Fetuin-A with Insulin Sensitivity in Young Women

2020 ◽  
Vol 52 (11) ◽  
pp. 809-814
Author(s):  
Sabrina Reif ◽  
Sarah Moschko ◽  
Christina Gar ◽  
Uta Ferrari ◽  
Nina Hesse ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Young Women ◽  
Fat Content ◽  
Liver Fat ◽  
Liver Fat Content ◽  
Fetuin A ◽  
The Metabolic Syndrome ◽  
Independent Association

AbstractAnimal data link high circulating fetuin-A to low insulin sensitivity and observational studies identify the hepatokine as a marker of future incident type 2 diabetes mellitus in humans. However, a recent, well-powered Mendelian randomization study finds no causal role. We therefore tested in a deeply-phenotyped human cohort if circulating fetuin-A correlates independently with insulin sensitivity and how it relates to the metabolic syndrome and ectopic fat deposition. We analyzed data from 290 young women with and without recent gestational diabetes mellitus. We found that circulating fetuin-A correlates inversely with insulin sensitivity in univariate analyses, but that this correlation is lost after adjustment for markers of the metabolic syndrome and of fatty liver. Additionally, we investigated which fat compartment associates most strongly with circulating fetuin-A. In whole body MRI data from a subcohort of 152 women, this was liver fat content. We conclude that high circulating fetuin-A occurs as part of the metabolic syndrome in young women and associates most strongly with liver fat content. Its close link to the metabolic syndrome may also cause the inverse correlation of circulating fetuin-A with insulin sensitivity as we found no independent association.

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