Adiponectin has been shown to stimulate fatty acid oxidation and enhance insulin sensitivity through the activation of AMP-activated protein kinase (AMPK) in the peripheral tissues. The effects of adiponectin in the central nervous system, however, are still poorly understood. Here, we show that adiponectin enhances AMPK activity in the arcuate hypothalamus (ARH) via its receptor AdipoR1 to stimulate food intake; this stimulation of food intake by adiponectin was attenuated by dominant-negative AMPK expression in the ARH. Moreover, adiponectin also decreased energy expenditure. Adiponectin-deficient mice showed decreased AMPK phosphorylation in the ARH, decreased food intake, and increased energy expenditure, exhibiting resistance to high-fat-diet-induced obesity. Serum and cerebrospinal fluid levels of adiponectin and expression of AdipoR1 in the ARH were increased during fasting and decreased after refeeding. We conclude that adiponectin stimulates food intake and decreases energy expenditure during fasting through its effects in the central nervous system.

In obese patients with type 2 diabetes, insulin delivery to and insulin-dependent glucose uptake by skeletal muscle are delayed and impaired. The mechanisms underlying the delay and impairment are unclear. We demonstrate that impaired insulin signaling in endothelial cells, due to reduced Irs2 expression and insulin-induced eNOS phosphorylation, causes attenuation of insulin-induced capillary recruitment and insulin delivery, which in turn reduces glucose uptake by skeletal muscle. Moreover, restoration of insulin-induced eNOS phosphorylation in endothelial cells completely reverses the reduction in capillary recruitment and insulin delivery in tissue-specific knockout mice lacking Irs2 in endothelial cells and fed a high-fat diet. As a result, glucose uptake by skeletal muscle is restored in these mice. Taken together, our results show that insulin signaling in endothelial cells plays a pivotal role in the regulation of glucose uptake by skeletal muscle. Furthermore, improving endothelial insulin signaling may serve as a therapeutic strategy for ameliorating skeletal muscle insulin resistance.

* Thiazolidinediones have been shown to up-regulate adiponectin expression in white adipose tissue and plasma adiponectin levels, and these up-regulations have been proposed to be a major mechanism of the thiazolidinedione-induced amelioration of insulin resistance linked to obesity. To test this hypothesis, we generated adiponectin knock-out (adipo) ob/ob mice with a C57B/6 background. After 14 days of 10 mg/kg pioglitazone, the insulin resistance and diabetes of ob/ob mice were significantly improved in association with significant up-regulation of serum adiponectin levels. Amelioration of insulin resistance in ob/ob mice was attributed to decreased glucose production and increased AMP-activated protein kinase in the liver but not to increased glucose uptake in skeletal muscle. In contrast, insulin resistance and diabetes were not improved in adipo ؊/؊ ob/ob mice. After 14 days of 30 mg/kg pioglitazone, insulin resistance and diabetes of ob/ob mice were again significantly ameliorated, which was attributed not only to decreased glucose production in the liver but also to increased glucose uptake in skeletal muscle. Interestingly, adipo ؊/؊ ob/ob mice also displayed significant amelioration of insulin resistance and diabetes, which was attributed to increased glucose uptake in skeletal muscle but not to decreased glucose production in the liver. The serum-free fatty acid and triglyceride levels as well as adipocyte sizes in ob/ob and adipo ؊/؊ ob/ob mice were unchanged after 10 mg/kg pioglitazone but were significantly reduced to a similar degree after 30 mg/kg pioglitazone. Moreover, the expressions of TNF␣ and resistin in adipose tissues of ob/ob and adipo ؊/؊ ob/ob mice were unchanged after 10 mg/kg pioglitazone but were decreased after 30 mg/kg pioglitazone. Thus, pioglitazone-induced amelioration of insulin resistance and diabetes may occur adiponectin dependently in the liver and adiponectin independently in skeletal muscle.

for the Brugada Syndrome Investigators in Japan Background-The prognosis of patients with saddleback or noncoved type (non-type 1) ST-elevation in Brugada syndrome is unknown. The purpose of this study was to clarify the long-term prognosis of probands with non-type 1 ECG and those with coved (type 1) Brugada-pattern ECG. Methods and Results-A total of 330 (123 symptomatic, 207 asymptomatic) probands with a coved or saddleback ST-elevation Ն1 mm in leads V 1 -V 3 were divided into 2 ECG groups-type 1 (245 probands) and non-type 1 (85 probands)-and were prospectively followed for 48.7Ϯ15.0 months. The absence of type 1 ECG was confirmed by drug provocation test and multiple recordings. The ratio of individuals with a family history of sudden cardiac death (14%) was lower than previous studies. Clinical profiles and outcomes were not notably different between the 2 groups (annual arrhythmic event rate of probands with ventricular fibrillation; type 1: 10.2%, non-type 1: 10.6%, probands with syncope; type 1: 0.6%, non-type 1: 1.2%, and asymptomatic probands; type 1: 0.5%, non-type 1: 0%). Family history of sudden cardiac death at age Ͻ45 years and coexistence of inferolateral early repolarization with Brugada-pattern ECG were independent predictors of fatal arrhythmic events (hazard ratio, 3.28; 95% confidence interval, 1.42 to 7.60; Pϭ0.005; hazard ratio, 2.66; 95% confidence interval, 1.06 to 6.71; Pϭ0.03, respectively, by multivariate analysis), although spontaneous type 1 ECG and ventricular fibrillation inducibility by electrophysiological study were not reliable parameters. Conclusions-The long-term prognosis of probands in non-type 1 group was similar to that of type 1 group. Family history of sudden cardiac death and the presence of early repolarization were predictors of poor outcome in this study, which included only probands with Brugada-pattern ST-elevation. (Circ Arrhythmia Electrophysiol. 2009;2:495-503.)