Obesity leads to a switch in subsets of CD4+ T cell in adipose tissue, characterized by an increase in IFNγ producing Th1 cells and a decrease in anti-inflammatory regulatory T (Treg) cells, which impairs systemic insulin sensitivity. What signals these changes is unknown. Herein we demonstrate that genetic deficiency of adipocyte MHCII decreases adipose IFNγ expression and increases adipose Treg abundance in obese mice, leading to reduced obesity-induced adipose inflammation and reduced insulin resistance without affecting weight gain. The preserved insulin sensitivity of high fat diet (HFD)-fed adipocyte-specific MHCII knockout (aMHCII−/−) mice was substantially attenuated by adipose-specific Treg ablation. Adipocytes of aMHCII−/− mice exhibit decreased capacity to stimulate IFNγ production in Th1 cells, whereas HFD-fed IFNγR1−/− mice were more insulin sensitive and had similarly high levels of Tregs in adipose tissue as aMHCII−/− mice. We further show that IFNγ strongly inhibits IL-33 effects to promote adipose Treg proliferation. Our results identify MHCII in adipocyte as a critical determinant of the obesity-induced adipose T cell subset switch and insulin resistance.

Although some studies suggest that a linear dose-response relationship exists between exercise and insulin sensitivity, the exercise dose required to enhance pancreatic β-cell function is unknown. Thirty-five older obese adults with prediabetes underwent a progressive 12-wk supervised exercise intervention (5 days/wk for 60 min at ~85% HRmax). Insulin and C-peptide responses to an OGTT were used to define the first- and second-phase disposition index (DI; β-cell function = glucose-stimulated insulin secretion × clamp-derived insulin sensitivity). Maximum oxygen consumption (Vo2max) and body composition (dual-energy X-ray absorptiometry and computed tomography) were also measured before and after the intervention. Exercise dose was computed using Vo2/heart-rate derived linear regression equations. Subjects expended 474.5 ± 8.8 kcal/session (2,372.5 ± 44.1 kcal/wk) during the intervention and lost ~8% body weight. Exercise increased first- and second-phase DI (P < 0.05), and these changes in DI were linearly related to exercise dose (DIfirst phase: r = 0.54, P < 0.001; DIsecond phase: r = 0.56, P = 0.0005). Enhanced DI was also associated with increased Vo2max (DIfirst phase: r = 0.36, P = 0.04; DIsecond phase: r = 0.41, P < 0.02) but not lower body fat (DIfirst phase: r = -0.21, P = 0.25; DIsecond phase: r = -0.30, P = 0.10) after training. Low baseline DI predicted an increase in DI after the intervention (DIfirst phase: r = -0.37; DIsecond phase: r = -0.41, each P < 0.04). Thus, exercise training plus weight loss increased pancreatic β-cell function in a linear dose-response manner in adults with prediabetes. Our data suggest that higher exercise doses (i.e., >2,000 kcal/wk) are necessary to enhance β-cell function in adults with poor insulin secretion capacity.

Malin SK, Haus JM, Solomon TP, Blaszczak A, Kashyap SR, Kirwan JP. Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes. Am J Physiol Endocrinol Metab 305: E1292-E1298, 2013. First published September 24, 2013; doi:10.1152/ajpendo.00441.2013.-Impaired fasting glucose (IFG) blunts the reversal of impaired glucose tolerance (IGT) after exercise training. Metabolic inflexibility has been implicated in the etiology of insulin resistance; however, the efficacy of exercise on peripheral and hepatic insulin sensitivity or substrate utilization in adults with IFG, IGT, or IFG ϩ IGT is unknown. Twenty-four older (66.7 Ϯ 0.8 yr) obese (34.2 Ϯ 0.9 kg/m 2 ) adults were categorized as IFG (n ϭ 8), IGT (n ϭ 8), or IFG ϩ IGT (n ϭ 8) according to a 75-g oral glucose tolerance test (OGTT). Subjects underwent 12-wk of exercise (60 min/day for 5 days/wk at ϳ85% HRmax) and were instructed to maintain a eucaloric diet. A euglycemic hyperinsulinemic clamp (40 mU·m 2 ·min Ϫ1 ) with [6,6-2 H]glucose was used to determine peripheral and hepatic insulin sensitivity. Nonoxidative glucose disposal and metabolic flexibility [insulin-stimulated respiratory quotient (RQ) minus fasting RQ] were also assessed. Glucose incremental area under the curve (iAUCOGTT) was calculated from the OGTT. Exercise increased clamp-derived peripheral and hepatic insulin sensitivity more in adults with IFG or IGT alone than with IFG ϩ IGT (P Ͻ 0.05). Exercise reduced glucose iAUCOGTT in IGT only (P Ͻ 0.05), and the decrease in glucose iAUCOGTT was inversely correlated with the increase in peripheral but not hepatic insulin sensitivity (P Ͻ 0.01). Increased clamp-derived peripheral insulin sensitivity was also correlated with enhanced metabolic flexibility, reduced fasting RQ, and higher nonoxidative glucose disposal (P Ͻ 0.05). Adults with IFG ϩ IGT had smaller gains in clamp-derived peripheral insulin sensitivity and metabolic flexibility, which was related to blunted improvements in postprandial glucose. Additional work is required to assess the molecular mechanism(s) by which chronic hyperglycemia modifies insulin sensitivity following exercise training. obesity; prediabetes; insulin resistance; cardiometabolic; exercise APPROXIMATELY 79 MILLION ADULTS in the US have impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both (IFG ϩ IGT) and are collectively referred to as having prediabetes (2). Focusing on adults with IFG, IGT, and IFG ϩ IGT is clinically important since each phenotype has a unique pathology that promotes different degrees of cardiovascular disease risk (8, 31). The exact cause for the difference in disease risk is unclear, but the degree of insulin resistance in skeletal muscle or the liver is a likely candidate. Individuals with IGT [2-h oral glucose tolerance test (OGTT) values between 140 and 199 mg/dl] are typically characterized as having reduced skeletal muscle insulin sensitivity, whereas adults with IFG (fasting glucose 100 -125 mg/dl) generally h...

The role of adipose tissue (AT) inflammation in obesity and its multiple related-complications is a rapidly expanding area of scientific interest. Within the last 30 years, the role of the adipocyte as an endocrine and immunologic cell has been progressively established. Like the macrophage, the adipocyte is capable of linking the innate and adaptive immune system through the secretion of adipokines and cytokines; exosome release of lipids, hormones, and microRNAs; and contact interaction with other immune cells. Key innate immune cells in AT include adipocytes, macrophages, neutrophils, and innate lymphoid cells type 2 (ILC2s). The role of the innate immune system in promoting adipose tissue inflammation in obesity will be highlighted in this review. T cells and B cells also play important roles in contributing to AT inflammation and are discussed in this series in the chapter on adaptive immunity.

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