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The pregnane X receptor (PXR), along with its sister receptor constitutive androstane receptor (CAR), was initially characterized as a xenobiotic receptor that regulates drug metabolism. In this study, we have uncovered an unexpected endobiotic role of PXR in obesity and type 2 diabetes. PXR ablation inhibited high-fat diet (HFD)--induced obesity, hepatic steatosis, and insulin resistance, which were accounted for by increased oxygen consumption, increased mitochondrial b-oxidation, inhibition of hepatic lipogenesis and inflammation, and sensitization of insulin signaling. In an independent model, introducing the allele PXR-/- into the / background also improved body composition and relieved the diabetic phenotype. The / mice deficient of PXR showed increased oxygen consumption and energy expenditure, as well as inhibition of gluconeogenesis and increased rate of glucose disposal during euglycemic clamp. Mechanistically, the metabolic benefits of PXR ablation were associated with the inhibition of c-Jun NH2-terminal kinase activation and downregulation of lipin-1, a novel PXR target gene. The metabolic benefit of PXR ablation was opposite to the reported prodiabetic effect of CAR ablation. Our results may help to establish PXR as a novel therapeutic target, and PXR antagonists may be used for the prevention and treatment of obesity and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Obesity-associated increases in adipose tissue (AT) CD11c+ cells suggest that dendritic cells (DC), which are involved in the tissue recruitment and activation of macrophages, may play a role in determining AT and liver immunophenotype in obesity. This study addressed this hypothesis. With the use of flow cytometry, electron microscopy, and loss-and-gain of function approaches, the contribution of DC to the pattern of immune cell alterations and recruitment in obesity was assessed. In AT and liver there was a substantial, high-fat diet (HFD)-induced increase in DC. In AT, these increases were associated with crown-like structures, whereas in liver the increase in DC constituted an early and reversible response to diet. Notably, mice lacking DC had reduced AT and liver macrophages, whereas DC replacement in DC-null mice increased liver and AT macrophage populations. Furthermore, delivery of bone marrow-derived DC to lean wild-type mice increased AT and liver macrophage infiltration. Finally, mice lacking DC were resistant to the weight gain and metabolic abnormalities of an HFD. Together, these data demonstrate that DC are elevated in obesity, promote macrophage infiltration of AT and liver, contribute to the determination of tissue immunophenotype, and play a role in systemic metabolic responses to an HFD. [ABSTRACT FROM AUTHOR]

Estrogen sulfotransferase (EST), the enzyme responsible for the sulfonation and inactivation of estrogens, plays an important role in estrogen homeostasis. In this study, we showed that induction of hepatic Est is a common feature of type 2 diabetes. Loss of Est in female mice improved metabolic function in ob/ob, dexamethasone-, and high-fat diet--induced mouse models of type 2 diabetes. The metabolic benefit of Est ablation included improved body composition, increased energy expenditure and insulin sensitivity, and decreased hepatic gluconeogenesis and lipogenesis. This metabolic benefit appeared to have resulted from decreased estrogen deprivation and increased estrogenic activity in the liver, whereas such benefit was abolished in ovariectomized mice. Interestingly, the effect of Est was sex-specific, as Est ablation in ob/ob males exacerbated the diabetic phenotype, which was accounted for by the decreased islet β-cell mass and failure of glucose-stimulated insulin secretion in vivo. The loss of β-cell mass in ob/ob males deficient in Est was associated with increased macrophage infiltration and inflammation in white adipose tissue. Our results revealed an essential role of EST in energy metabolism and the pathogenesis of type 2 diabetes. Inhibition of EST, at least in females, may represent a novel approach to manage type 2 diabetes. [ABSTRACT FROM AUTHOR]

The prevalence of nonalcoholic fatty liver disease (NAFLD) in the general population has been increasing, concomitant with the rise of obesity. NAFLD is associated with hypertriglyceridemia and hepatic insulin resistance and predisposes towards the development of steatohepatitis and liver failure. We have previously shown that increased fatty acid (FA) oxidation reduces liver triglyceride (TG) content in rats fed a standard chow diet. This was achieved by elevating the activity of the liver form of camitine palmitoyltransferase I (L-CPT I), the rate determining step of FA oxidation. In the current study, we addressed the effects of increasing hepatic activity of L-CPT I, on liver, muscle (gastrocnemius) and plasma triglyceride levels, liver FA oxidation, and other plasma metabolic variables in a rat model of diet-induced obesity and steatosis. Age and weight-matched male Sprague-Dawley rats (n=l 7) were placed on a high fat diet for 6 weeks prior to receiving a recombinant adenovirus (1 x 10 [sup 12] pfu) containing the L-CPT I cDNA (Adv-L-CPT I) (n=9) or a control adenovirus (1 x 10 [sup 12] pfu, n=8). Five days after viral transduction, animals were fasted overnight, anesthetized, and tissues and plasma harvested for analysis. Liver TG content was reduced by 56 ± 10% (p=0.003) in Adv-L-CPT 1 animals vs. controls, while plasma TG content was increased by 77 ± 22% (p=0.003). Muscle TG content was similar between the two groups. Liver CPT I activity and FA oxidation were increased by 62 ± 10% (p<0.001) and 36 ± 6% (p=0.006), respectively, in ADV-L-CPT I animals compared to controls. There was a trend toward decreased levels of plasma insulin (23 ±11%, p=0.44) and free FAs (26 ±20%, p=0.51) in Adv-L-CPT I animals, which did not reach statistical significance. Plasma glucose levels were similar between two groups. Together, these data demonstrate that a modest increase in L-CPT I activity stimulates hepatic FA oxidation and reduces diet-induced liver steatosis, and suggest that therapeutic approaches stimulating L-CPT I activity may be beneficial in the treatment of NAFLD. [ABSTRACT FROM AUTHOR]

Weight loss and exercise-induced improvements in insulin resistance OR) am variable; some individuals experience robust enhancements in insulin sensitivity, while others do not. Thyroid hormone status is related to IR, but it is not clear whether subclinical hypothyroidism may help to explain the variability in improvements in IR. The purpose of this study was to examine the association between thyroid hormone status and the improvement in IR following exercise training in impaired glucose tolerant (IGT) subjects. Ten overweight to obese (BMI= 32 ±2.8 kg/m²) older (age=66.5±4.4 years) subjects completed a 16-week program consisting of 3-5 days per week, 30-45 min per session of moderate aerobic exercise (mostly walking). Insulin sensitivity, determined by a euglycemic hyperinsulinemic clamp, was measured before and after the intervention. A retrospective nested case control analysis was performed in subclinical hypothyroid (hypothyroid; N=5, TSH 4.38 ± 1.09 uIU/ml) versus normal thyroid (enthyroid; N=5, TSH 1.93 ±32 uIU/ml) subjects, matched on gender (3 women and 2 men in each group) and BMI. A 2x2 mixed ANOVA was performed on insuli a significant amount of body weight (∼6%, P≤0.001). These data suggest that despite a similar exercise program and weight loss, subclinical hypothyroidism may interfere with beneficial adaptations on muscle metabolism that typically occur with lifestyle modification. Further studies are needed to explore potential mechanisms that may underlie this blunted response in hypothyroid patients. ADA-Funded Research [ABSTRACT FROM AUTHOR]

Lifestyle modification, including a combination of weight loss and exercise, is especially effective in reducing the incidence of type 2 diabetes (T2DM) in older, high-risk individuals. However, the effects of exercise and diet-induced weight loss on insulin resistance and other cardiometabolic risk factors in older adults are not clear. The purpose of this study was to examine effects of weight loss and exercise, either alone or in combination, on insulin sensitivity and other cardiometabolic risk factors. Twenty-nine overweight/obese (BMI 31.8±3.2 kg⋅m[sup -2]) older (67.6±4.1 years) men (N=1 5) and women (N=14) with impaired glucose tolerance or newly diagnosed, drug-naïve T2DM were randomly assigned to one of the three lifestyle interventions: diet-induced weight loss (WL, N=9), exercise (EX, N=6) or combined weight loss and exercise (WL+EX, N=14). Insulin sensitivity, determined using a hyperinsulinemic (40 mU⋅m[sup -2]⋅min[sup -1]) euglycemic clamp, was improved (P<0.05) by each intervention: WL (23%), EX (26%) and WL+EX (31%). Fat mass, determined by DEXA, was decreased (P<0.05) following each intervention: WL (-18%), EX (-6%) and WL+EX (-19%). While no changes were observed in serum cholesterol or triglycerides, both systolic (WL -12%, EX -12% and WL+EX -11%) and diastolic (WL -8%, EX - 13%, and WL+EX -15%) were decreased (P<0.05) following intervention. C-reactive protein was decreased in WL (-28%) and WL+EX (-41%), but increased in EX (13%), all P<0.05. Changes in physical fitness (VO[sub 2max]) better predicted (r²=0.23, P<0.05) changes in insulin sensitivity than changes in fat-mass (r²=0.03, P=ns). In conclusion, diet-induced weight loss and exercise training independently, but not additively, improve insulin resistance, hypertension and inflammatory status in older adults with or at risk for developing T2DM. Additionally, enhanced aerobic fitness is a better predictor of improved insulin action than are changes in overall fat mass. ADA-Funded Research [ABSTRACT FROM AUTHOR]