Grant: Project Grant

Obesity is a major health problem worldwide, as it increases the risk for cardiovascular diseases, type II diabetes, certain cancers etc. The main cause of obesity is excess intake of high-calorie food and sedentary lifestyle. As the brain controls food intake and energy expenditure, in particular a region called the hypothalamus, it is important to understand how high fat food affects the hypothalamus to promote weight gain. It has become clear that high fat diet (HFD) induces inflammation of the hypothalamus. Importantly, this inflammation causes excess food intake and obesity. However, how hypothalamic inflammation affects body weight regulation remains poorly understood. One key cell population in the hypothalamus is melanin-concentrating hormone (MCH) neurons that promote food intake. Our preliminary study using rodent models suggests that a certain inflammatory mediator (prostaglandin E2; PGE2) is induced by HFD and activates MCH neurons. This results in more food intake and weight gain. Based on this exciting finding, we propose to address the hypothesis: "HFD-induced hypothalamic inflammation increases food intake and body weight by directly activating MCH neurons". Aim 1: We will elucidate the effect of HFD on PGE2 production in the hypothalamus. This will be the first study to investigate the role of hypothalamic PGE2 in diet-induced obesity. Aim 2: Cellular mechanisms underlying HFD-induced changes in MCH neurons will be investigated, with a focus on PGE2 signaling. Aim 3: We will test whether blocking PGE2 signaling in MCH neurons can alleviate diet-induced obesity. The proposed study will explain why HFD-induced inflammation induces obesity. Given the prevalence and impact of obesity on our health and society, it is important to determine the consequences of diet-induced hypothalamic inflammation and discover novel therapeutic targets for obesity.