Independent tissue contributors to obesity-associated insulin resistance

Kusters, Yvo H A M; Schalkwijk, Casper G.; Houben, Alfons J.H.M.; Kooi, M. Eline; Lindeboom, Lucas; Roodt, Jos Op ‘t; Joris, Peter J.; Mensink, Ronald P.; Barrett, Eugene J.; Stehouwer, Coen D. A.

doi:10.1172/jci.insight.89695

Cited by 30 publications

(50 citation statements)

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“…To our knowledge, this is the first study to evaluate the relationships among robust assessments of metabolic function, body composition and fat distribution, and objective measures of physical fitness in healthy nonobese Asians. In contrast, previous investigations have been conducted in individuals who were either overweight or obese, had clinical features of metabolic dysfunction, such as hyperglycaemia, diabetes, dyslipidaemia and hypertension, or—most commonly—were of Western descent . Our findings suggest there is a need to develop effective strategies to encourage participation in vigorous exercise to improve aerobic fitness, body composition and metabolic function in nonobese Asians who could potentially be at risk of diabetes.…”

Section: Discussioncontrasting

confidence: 70%

“…In contrast, previous investigations have been conducted in individuals who were either overweight or obese, 20 had clinical features of metabolic dysfunction, such as hyperglycaemia, diabetes, dyslipidaemia and hypertension, 21,22 or-most commonly-were of Western descent. 9,11,23 Our findings suggest there is a need to develop effective strategies to encourage participation in vigorous exercise to improve aerobic fitness, body composition and metabolic function in nonobese Asians who could potentially be at risk of diabetes.…”

Section: Discussionmentioning

confidence: 88%

“…Kusters et al on the other hand, identified mutually independent contributions of VAT and IHTG on whole‐body glucose disposal in healthy lean men. Nevertheless, it was found that only a reduction in IHTG content contributed to improved insulin sensitivity following weight loss in obese men . It is thus possible that inherent differences exist between lean and obese individuals with regards to the importance of ectopic fat depots in affecting metabolic function.…”

Section: Discussionmentioning

confidence: 99%

“…Substantial research has established the importance of ectopic fat deposition and physical inactivity in the pathogenesis of insulin resistance and beta cell dysfunction in United States and European subjects with a wide range of BMI and glycaemic control . Nevertheless, the relevance of these factors to nonobese Asians is not clear, because body fat distribution, physical activity patterns and metabolic function differ considerably between Western and Asian populations .…”

Section: Introductionmentioning

confidence: 99%

“…8 Substantial research has established the importance of ectopic fat deposition and physical inactivity in the pathogenesis of insulin resistance and beta cell dysfunction in subjects from the United States and European subjects with a wide range of BMI and glycaemic control. [9][10][11] Nevertheless, the relevance of these factors to nonobese Asians is not clear, 12 because body fat distribution, physical activity patterns and metabolic function differ considerably between Western and Asian populations. 13,14 To this end, we conducted a cross-sectional study and used state-of-the-art imaging techniques and metabolic function tests to assess the relationships between insulin sensitivity, insulin secretion, body fat distribution and physical fitness in healthy nonobese Asian subjects.…”

Section: Introductionmentioning

confidence: 99%

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Ectopic fat and aerobic fitness are key determinants of glucose homeostasis in nonobese Asians

Chan

Ding

Chooi

et al. 2019

Eur J Clin Investigation

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Background The importance of ectopic fat deposition and physical fitness in the pathogenesis of insulin resistance and beta cell dysfunction in subjects from the nonobese Asians is not known. Materials and methods We conducted a cross‐sectional study and measured insulin sensitivity (M value; 4‐hour hyperinsulinaemic‐euglycaemic clamp), insulin secretion rate (3‐hour mixed meal tolerance test with oral minimal modelling), percent body fat, visceral adipose tissue, intramyocellular and intrahepatic lipid contents (magnetic resonance imaging and spectroscopy), cardiorespiratory fitness (VO2max; graded exercise test) and habitual physical activity (short International Physical Activity Questionnaire) in 60 healthy nonobese Asian subjects (BMI = 21.9 ± 1.7 kg/m2, age = 41.8 ± 13.4 years). Results M was inversely associated with percent body fat (r = −0.460, P < 0.001), visceral fat (r = −0.623, P < 0.001) and liver fat (r = −0.601, P < 0.001), whereas insulin secretion correlated positively with these adiposity indices (percent body fat: r = 0.303, P = 0.018; visceral fat: r = 0.409, P = 0.010; hepatic fat: r = 0.393, P = 0.002). VO2max correlated negatively with insulin secretion rate (r = −0.420, P < 0.001) and positively with M (r = 0.658, P < 0.001). The amount of vigorous physical activity was positively associated with VO2max (r = 0.682, P < 0.001). Multiple stepwise linear regression analyses indicated that VO2max, age, and IHTG or VAT were independent determinants of insulin sensitivity and secretion (adjusted R2 = 69% and 33%, respectively, P < 0.001). Conclusions Increased ectopic fat deposition is associated with reduced insulin sensitivity and increased insulin secretion in healthy nonobese Asians. Poor cardiorespiratory fitness, likely due to inadequate participation in vigorous exercise, is strongly related to suboptimal metabolic function. Interventions to encourage engagement in physical activity may thus be important for improving metabolic health in nonobese Asians.

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Section: Discussioncontrasting

confidence: 70%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ectopic fat and aerobic fitness are key determinants of glucose homeostasis in nonobese Asians

Chan

Ding

Chooi

et al. 2019

Eur J Clin Investigation

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NK cells in human visceral adipose tissue contribute to obesity‐associated insulin resistance through low‐grade inflammation

Wouters

Kusters

Bijnen

et al. 2020

Clinical & Translational Med

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Dear Editor, Obesity leads to macrophage infiltration in adipose tissue (AT), causing chronic low-grade inflammation (LGI). This in turn leads to insulin resistance, contributing to F I G U R E 1 NK cells from obese subjects promote inflammatory macrophage polarization and produce increased levels of TNF. A, Bloodderived NK cells from control (n = 6; BMI 24.0 [22.5-26.2] kg/m 2 ; white bars) and obese individuals (n = 8; BMI 41.5 [40.4-47.0] kg/m 2 ; black bars) were isolated and co-cultured with either human monocyte derived macrophages to analyze surface expression of M1 markers (CCR7, CD86, and CD64), or incubated with macrophages that were first polarized to an M2 phenotype and assessed for loss of M2 markers (loss of CD209 and CD206; that is, polarization toward M1). An aggregate total effect of polarization toward an M1 phenotype was calculated (ie, a z-score composed of the individual z-scores of-CD209,-CD206, CCR7, CD86, and CD64). Compared to lean individuals, NK cells from obese individuals induced macrophage polarization toward the M1 phenotype (mean difference 1.08 SD [95% CI 0.06-2.10 SD; * P < .05]). Data are presented as mean ± SEM. B, Intracellular TNF levels were measured in blood-derived NK cells of lean (n = 4) and obese individuals (n = 6) using flow cytometry. Box plot is as follows: black line, median; box edges, first and third quartiles; whiskers, minimum, and maximum of all data. C, Association between CD11B surface expression and intracellular TNF levels of blood-derived NK cells (n = 8). Pearson's correlation coefficient, regression coefficient, and their P-value are reported This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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A randomized diet‐induced weight‐loss intervention reduces plasma complement C3: Possible implication for endothelial dysfunction

Jin

Kusters

Houben

et al. 2022

Obesity

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ObjectiveComplement C3 and other components of the alternative pathway are higher in individuals with obesity. Moreover, C3 has been identified as a risk factor for cardiovascular disease. This study investigated whether, and how, a weight‐loss intervention reduced plasma C3, activated C3 (C3a), and factor D and explored potential biological effects of such a reduction.MethodsThe study measured plasma C3, C3a, and factor D by ELISA and measured visceral adipose tissue, subcutaneous adipose tissue, and intrahepatic lipid by magnetic resonance imaging in lean men (n = 25) and men with abdominal obesity (n = 52). The men with obesity were randomized to habitual diet or an 8‐week dietary weight‐loss intervention.ResultsThe intervention significantly reduced C3 (−0.15 g/L [95% CI: −0.23 to −0.07]), but not C3a or factor D. The C3 reduction was mainly explained by reduction in visceral adipose tissue but not subcutaneous adipose tissue or intrahepatic lipid. This reduction in C3 explained a part of the weight‐loss‐induced improvement of markers of endothelial dysfunction, particularly the reduction in soluble endothelial selectin and soluble intercellular adhesion molecule.ConclusionsDiet‐induced weight loss in men with abdominal obesity could be a way to lower plasma C3 and thereby improve endothelial dysfunction. C3 reduction may be part of the mechanism via which diet‐induced weight loss could ameliorate the risk of cardiovascular disease in men with abdominal obesity.

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Independent tissue contributors to obesity-associated insulin resistance

Cited by 30 publications

References 31 publications

Ectopic fat and aerobic fitness are key determinants of glucose homeostasis in nonobese Asians

Ectopic fat and aerobic fitness are key determinants of glucose homeostasis in nonobese Asians

NK cells in human visceral adipose tissue contribute to obesity‐associated insulin resistance through low‐grade inflammation

A randomized diet‐induced weight‐loss intervention reduces plasma complement C3: Possible implication for endothelial dysfunction

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