In contrast to the well-established role of oxidative muscle fibers in regulating whole-body metabolism, little is known about the function of fast/glycolytic muscle fibers in these processes. Here, we generated a skeletal muscle-specific, conditional transgenic mouse expressing a constitutively active form of Akt1. Transgene activation led to muscle hypertrophy due to the growth of type IIb muscle fibers, which was accompanied by an increase in strength. Akt1 transgene induction in diet-induced obese mice led to reductions in body weight and fat mass, resolution of hepatic steatosis, and improved metabolic parameters. Akt1-mediated skeletal muscle growth opposed the effects of a high-fat/high-sucrose diet on transcript expression patterns in the liver and increased hepatic fatty acid oxidation and ketone body production. Our findings indicate that an increase in fast/glycolytic muscle mass can result in the regression of obesity and metabolic improvement through its ability to alter fatty acid oxidation in remote tissues.

Background-Chronic hypoxic pulmonary hypertension (CH-PHT) is associated with suppressed expression and function of voltage-gated K ϩ channels (Kv) in pulmonary artery (PA) smooth muscle cells (SMCs) and a shift in cellular redox balance toward a reduced state. We hypothesized that dichloroacetate (DCA), a metabolic modulator that can shift redox balance toward an oxidized state and increase Kv current in myocardial cells, would reverse CH-PHT. Methods and Results-We studied 4 groups of rats: normoxic, normoxicϩDCA (DCA 70 mg · kg Ϫ1 · d Ϫ1 PO), chronically hypoxic (CH), and CHϩDCA. CH and CHϩDCA rats were kept in a hypoxic chamber (10% FiO 2 ) for 2 to 3 weeks. DCA was given either at day 1 to prevent or at day 10 to reverse CH-PHT. We used micromanometer-tipped catheters and measured hemodynamics in closed-chest rats on days 14 to 18. CHϩDCA rats had significantly reduced pulmonary vascular resistance, right ventricular hypertrophy, and PA remodeling compared with the CH rats. CH inhibited I K , eliminated the acute hypoxia-sensitive I K , and decreased Kv2.1 channel expression. In the short term, low-dose DCA (1 mol/L) increased I K in CH-PASMCs. In a mammalian expression system, DCA activated Kv2.1 by a tyrosine kinase-dependent mechanism. When given long-term, DCA partially restored I K and Kv2.1 expression in PASMCs without altering right ventricular pyruvate dehydrogenase activity, suggesting that the beneficial effects of DCA occur by nonmetabolic mechanisms. Conclusions-DCA both prevents and reverses CH-PHT by a mechanism involving restoration of expression and function of Kv channels. DCA has previously been used in humans and may potentially be a therapeutic agent for pulmonary hypertension. (Circulation. 2002;105:244-250.)

Obesity is strongly associated with the pathogenesis of type 2 diabetes, hypertension, and cardiovascular disease. Levels of the hormone adiponectin are downregulated in obese individuals, and several experimental studies show that adiponectin protects against the development of various obesity-related metabolic and cardiovascular diseases. Adiponectin exhibits favorable effects on atherogenesis, endothelial function, and vascular remodeling by modulation of signaling cascades in cells of the vasculature. More recent findings have shown that adiponectin directly affects signaling in cardiac cells and is beneficial in the setting of pathological cardiac remodeling and acute cardiac injury. Several of these effects of adiponectin have been attributed to the activation of the 5' AMP-activated protein kinase signaling cascade and other signaling proteins. This review will discuss the epidemiological and experimental studies that have elucidated the role of adiponectin in a variety of cardiovascular diseases.

Background-Acute pharmacological inhibition of cardiac malonyl coenzyme A decarboxylase (MCD) protects the heart from ischemic damage by inhibiting fatty acid oxidation and stimulating glucose oxidation. However, it is unknown whether chronic inhibition of MCD results in altered cardiac function, energy metabolism, or ischemic cardioprotection. Methods and Results-Mcd-deficient mice were produced and assessed for in vivo cardiac function as well as ex vivo cardiac function, energy metabolism, and ischemic tolerance. In vivo and ex vivo cardiac function was similar in wild-type and mcd Ϫ/Ϫ mice. Ex vivo working hearts from mcd Ϫ/Ϫ and wild-type mice displayed no significant differences in rates of fatty acid oxidation, glucose oxidation, or glycolysis. However, cardiac deletion of mcd resulted in an increased expression of genes regulating fatty acid utilization that may compensate for the loss of MCD protein and likely contributes to the absence of changes in energy metabolism in the aerobic heart. Despite the lack of changes in fatty acid utilization, hearts from mcd Ϫ/Ϫ mice displayed a marked preference for glucose utilization after ischemia, which correlated with a significant cardioprotection of ischemic hearts from mcd Ϫ/Ϫ mice compared with wild-type mice. Conclusions-Deletion of MCD markedly increases glucose oxidation and improves functional recovery of the heart after ischemia. As a result, chronic pharmacological inhibition of MCD may be a viable approach to treat myocardial ischemia. (Circulation. 2006;114:1721-1728.)

OBJECTIVE-Peroxisome proliferator-activated receptors (PPARs) are therapeutic targets for fibrates and thiazolidinediones, which are commonly used to ameliorate hyperlipidemia and hyperglycemia in type 2 diabetes. In this study, we evaluated whether activation of PPAR␣ and PPAR␥ stimulates neoangiogenesis.RESEARCH DESIGN AND METHODS-We used selective synthetic PPAR␣ and PPAR␥ agonists and investigated their angiogenic potentials in vitro and in vivo.RESULTS-Activation of PPAR␣ and PPAR␥ leads to endothelial tube formation in an endothelial/interstitial cell co-culture assay. This effect is associated with increased production of the angiogenic cytokine vascular endothelial growth factor (VEGF). Neovascularization also occurs in vivo, when PPAR␣ and PPAR␥ agonists are used in the murine corneal angiogenic model. No vascular growth is detectable when PPAR␣ and PPAR␥ agonists are respectively used in PPAR␣ knockout mice and mice treated with a specific PPAR␥ inhibitor, demonstrating that this angiogenic response is PPAR mediated. PPAR␣-and PPAR␥-induced angiogenesis is associated with local VEGF production and does not differ in extent and morphology from that induced by VEGF. In addition, PPAR␣-and PPAR␥-induced in vitro and in vivo angiogenesis may be significantly decreased by inhibiting VEGF activity. Finally, in corneas treated with PPAR␣ and PPAR␥ agonists, there is increased phosphorylation of endothelial nitric oxide synthase and Akt.CONCLUSIONS-These findings demonstrate that PPAR␣ and PPAR␥ activation stimulates neoangiogenesis through a VEGFdependent mechanism. Neoangiogenesis is a crucial pathological event in type 2 diabetes. The ability of PPAR␣ and PPAR␥ agonists to induce neoangiogenesis might have important implications for the clinical and therapeutic management of type 2 diabetes. Diabetes 57:1394-1404, 2008 P eroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors that belong to the nuclear hormone receptor superfamily (1). The clinical importance of PPARs originates with fibrates and thiazolidinediones (TZDs), which respectively act on PPAR␣ and PPAR␥ and are used to ameliorate hyperlipidemia and hyperglycemia in subjects with type 2 diabetes. Fibrates (gemfibrozil, clofibrate, fenofibrate, and bezofibrate) are drugs that effectively reduce triglycerides (TGs) and free fatty acids (FFAs) and increase HDL cholesterol (2-5). Fibrates also improve glucose tolerance in type 2 diabetic patients, although this activity might be attributable to the fact that some of these compounds also have potential PPAR␥ activity (6). TZDs (such as rosiglitazone, troglitazone, pioglitazone, and ciglitazone) are insulin-sensitizing drugs and have constituted a major advance in the recent therapeutic management of type 2 diabetes (7-9). In addition to improving insulin sensitivity, TZDs have also effects on TG, FFA, and ketone body level in several animal models of type 2 diabetes. Recently, PPAR␣/␥ dual agonists have also been produced, hypothesizing that the simultaneous activa...