Impaired Transient Receptor Potential Vanilloid Type-1 Signaling Promotes Obesity and Leptin/Insulin Resistance In Mice

Abstract

According to prevalence of obesity and its-associated metabolic disorders worldwide, these diseases become severe and global health problem. Obesity defined as a condition accumulated excess fat mass bodily is a hall marker and major cause of metabolic diseases such as cardiovascular disease, stroke, and type 2 diabetes (T2D). Because obesity and T2D patients have dramatically higher risks of cardiovascular disease, the most common cause of death in Western countries, an increase in the prevalence of obesity and diabetes in the population is one of the most serious problems of modern society. Thus, the prevention and treatment of obesity and T2D become more and more important. Insulin resistance, an attenuated or lack of response of the insulin receptor (IR) and its downstream signaling pathway to insulin stimulation even at high doses of insulin, is a representative characteristic of T2D. Although insulin resistance is caused by inflammation, oxidative stress, ER stress, and mitochondrial dysfunction, the specific mechanisms which lead from obesity to T2D is still unclear. Recent evidences have been clearly showed that capsaicin, a pungent component of chili peppers, play a crucial role in obesity and metabolic disorders. Administration of capsaicin prevents obesity and improves glucose homeostasis and insulin secretion in small rodents and humans. Several previous studies have reported supportive clinical evidence that consumption of red peppers or capsaicin was shown to decrease appetite, cause weight loss and stimulate thermogenesis caused by substrate oxidation from carbohydrate to fat oxidation. However, the role of its receptor, transient receptor potential vanilloid subfamily type 1 (TRPV1), in development of obesity and its- associated insulin resistance is controversial, which suggests that its specific function and mechanistic studies in metabolic disorders are poorly understood. Here, I examined the effect of TRPV1, capsaicin receptor, on diet-induced obesity and insulin resistance in mice. TRPV1-deficient mice became more obese and get more fat accumulation on high-fat diet (HFD) feeding than wild-type (WT) mice. These results were caused by reduced locomotor activity in TRPV1 KO mice fed HFD for 5 weeks. In TRPV1 KO mice, plasma leptin levels were decreased. Although leptin up-regulates locomotor activity as well as energy expenditure, TRPV1 KO mice showed decreased activity and no changes in energy expenditure compared to WT mice, suggesting severe leptin resistance in TRPV1 KO mice fed HFD. All of these results indicated that TRPV1 is a regulator of energy balance and development of leptin resistance in obese mice. In addition, TRPV1 deletion accelerates diet-induced insulin resistance. Insulin-stimulated glucose uptake in adipose tissues and heart was significantly diminished in HFD-fed TRPV1 KO mice. As one of the major causes of inflammation, oxidative stress and mitochondrial dysfunction, aging has been showed to induce obesity and insulin resistance. Deletion of TRPV1 in mice accelerated aging-induced weight gain and insulin resistance. Unlike the results fed HFD, aging promoted hepatic insulin resistance in TRPV1 KO mice compared to WT mice. Thus, these results provide new insight into the involvement of TRPV1 in development of obesity and insulin resistance and promising strategy against their pathogenesis.