Diabetic heart failure may be causally associated with alterations in cardiac energy metabolism and insulin resistance. Mice with heart-specific overexpression of peroxisome proliferator-activated receptor (PPAR)␣ showed a metabolic and cardiomyopathic phenotype similar to the diabetic heart, and we determined tissuespecific glucose metabolism and insulin action in vivo during hyperinsulinemic-euglycemic clamps in awake myosin heavy chain (MHC)-PPAR␣ mice (12-14 weeks of age). Basal and insulin-stimulated glucose uptake in heart was significantly reduced in the MHC-PPAR␣ mice, and cardiac insulin resistance was mostly attributed to defects in insulin-stimulated activities of insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase, Akt, and tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3). Interestingly, MHC-PPAR␣ mice developed hepatic insulin resistance associated with defects in insulin-mediated IRS-2-associated PI 3-kinase activity, increased hepatic triglyceride, and circulating interleukin-6 levels. To determine the underlying mechanism, insulin clamps were conducted in 8-week-old MHC-PPAR␣ mice. Insulin-stimulated cardiac glucose uptake was similarly reduced in 8-week-old MHC-PPAR␣ mice without changes in cardiac function and hepatic insulin action compared with the age-matched wild-type littermates. Overall, these findings indicate that increased activity of PPAR␣, as occurs in the diabetic heart, leads to cardiac insulin resistance associated with defects in insulin signaling and STAT3 activity, subsequently leading to reduced cardiac function. Additionally, ageassociated hepatic insulin resistance develops in MHC-PPAR␣ mice that may be due to altered cardiac metabolism, functions, and/or inflammatory cytokines. Diabetes 54:2514 -2524, 2005 C ardiovascular disease is the leading cause of mortality in type 2 diabetes (1,2). Although the etiology of diabetic heart failure is poorly understood, there is a growing body of evidence (3-5) indicating that alterations in cardiac energy metabolism may precede and be causally associated with the development of cardiomyopathy in the diabetic heart. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily, and of the three identified mammalian PPAR subtypes (␣, ␥, and ␦), PPAR␣ regulates nuclear expression of genes involved in lipid metabolism in various cell types including heart (6,7). Since normal cardiac function is dependent on a constant rate of ATP resynthesis predominantly driven by mitochondrial fatty acid oxidation, activation of PPAR␣ by endogenous ligands, such as fatty acids, plays an important role in cardiac energy metabolism and functions (8,9). Mice with heart-specific overexpression of PPAR␣ (myosin heavy chain [MHC]-PPAR␣) were recently shown to exhibit increased rates of myocardial lipid oxidation, consistent with the role of PPAR␣ (10). Importantly, MHC-PPAR␣ mice developed cardiomyopathy with enh...

Obesity is a major public health issue worldwide and is frequently associated with erectile dysfunction (ED). Both conditions may share an internal pathologic environment, also known as common soil. Their main pathophysiologic processes are oxidative stress, inflammation, and resultant insulin and leptin resistance. Moreover, the severity of ED is correlated with comorbid medical conditions, including obesity. Therefore, amelioration of these comorbidities may increase the efficacy of ED treatment with phosphodiesterase 5 inhibitors, the first-line medication for patients with ED. Although metformin was originally developed as an insulin sensitizer six decades ago, it has also been shown to improve leptin resistance. In addition, metformin has been reported to reduce oxidative stress, inflammatory response, and body weight, as well as improve ED, in animal and human studies. Moreover, administration of a combination of metformin and phosphodiesterase 5 inhibitors improves erectile function in patients with ED who have a poor response to sildenafil and are insulin resistant. Thus, concomitant treatment of metabolic derangements associated with obesity in patients with ED who are obese would improve the efficacy and reduce the refractory response to penile vasodilators. In this review, we discuss the connecting factors between obesity and ED and the possible combined treatment modalities.

Although reactive oxygen species (ROS) are produced as a byproduct of oxygen metabolism, they play a significant role in normal cellular functions [1,2]. A well-organized antioxidant system maintains the physiological levels of ROS [3]. However, an imbalance between ROS production and antioxidant capacity causes ROS accumulation, which induces chemical modifications of DNA, protein, and lipids, leading to cellular damage, known as oxidative stress [1-3]. Oxidative stress is closely linked to a variety of diseases, including type 2 diabetes [1]. Type 2 diabetes is increasing globally due to the obesity pandemic and the growth of the aging population, and insulin resistance is a critical link between these two. Insulin resistance is known to be a critical risk factor for type 2 diabetes and other chronic diseases, such as cardiovascular diseases and cancers [4]. It is known that hyperglycemia in diabetic patients leads to se

PurposeHigh-fat (HF) feeding induces hypothalamic leptin resistance via the activation of toll-like receptor 4 (TLR4). TLR4 deficiency confers resistance to diet-induced obesity. Udenafil, an anti-impotence drug, inhibits TLR4 in airway epithelial cells in vitro. In this study, we evaluated whether udenafil suppressed the hypothalamic expression of TLR4 and reduced body weight.Materials and MethodsThe hypothalamic expression of TLR4, phosphodiesterase 5 (PDE5), nuclear factor-κB (NF-κB), and myeloid differentiation primary response gene 88 (Myd88) was analyzed by real-time polymerase chain reaction after treating mice for 2 days with udenafil (0, 12, 120, or 600 µg/d). Furthermore, the hypothalamic expression of TLR4, pro-opiomelanocortin (POMC), and neuropeptide Y (NPY) was analyzed after 9 days' treatment with udenafil and/or leptin. We also measured body weight and food intake following 9 days of udenafil and/or leptin treatment in control- and HF-fed mice.ResultsUdenafil suppressed hypothalamic TLR4 mRNA expression dose-dependently. The changes were associated with decreased PDE5, NF-κB, and Myd88 expression. Udenafil treatment for 9 days reduced body weight and caloric intake in HF-fed mice. This may have been associated with the suppression of NPY expression that was elevated by HF feeding. POMC expression was not affected by udenafil. However, udenafil did not augment the effects of leptin on the reduction of body weight and caloric intake in HF-fed mice.ConclusionsThese results suggested that udenafil reduced body weight by suppressing hypothalamic TLR4 mRNA expression in HF-fed mice and the combination effect of udenafil and leptin was additive rather than synergistic.

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