Role of thermoregulatory leptin action via the DMH in body weight control

描述（由申请人提供）：肥胖在世界范围内已经达到流行病的程度，特别是在像美国这样的繁荣国家。体重指数（BMI）超过30 kg/m2在临床上被定义为肥胖，并且显著增加了个体发展其他合并症的风险，这些合并症包括代谢综合征的“致命四重症”，包括II型糖尿病、高血压和高脂血症。在缺乏有效的干预策略来抑制肥胖，促进非寒颤产热（NST）已经重新出现作为一个潜在的可行的方法。NST通过从周围组织，特别是棕色脂肪组织（BAT）产生热量来消耗能量。尽管围绕BAT在控制成年人体重中的重要性存在争议，但BAT的大小已被发现与体重指数呈负相关，因此BAT产热的中枢调节因子可能是抗肥胖药物的潜在靶点。许多报告表明，瘦素，一种多效性脂肪细胞衍生的激素，可能通过中枢体温调节机制部分调节体重。事实上，已经证明下丘脑背内侧（DMH）的瘦素反应神经元概括了这种中枢体温调节途径。因此，我们假设表达DMH瘦素受体（LepRb）的神经元通过BAT NST调节能量消耗，并代表体重控制的间接手段。在这里，拟议的研究将使用迄今尚未用于体温调节研究领域的分子生物学最先进的工具，包括药物遗传学和光遗传学，来检测小鼠DMH中表达LepRb的神经元。这些研究的目的是促进我们对NST的理解并促进识别

DESCRIPTION (provided by applicant): Obesity has reached epidemic proportions across the world, particularly in prosperous nations like the United States. Having a body mass index (BMI) > 30 kg/m2 clinically defines an individual as obese and significantly increases that individual's risk of developing other co-morbidities that comprise the "deadly quartet" of metabolic syndrome, including type II diabetes, hypertension, and hyperlipidemia. In the absence of efficient intervention strategies for curbing obesity, the promotion of non-shivering thermogenesis (NST) has re- emerged as a potentially viable approach. NST expends energy by generating heat from peripheral tissues, particularly brown adipose tissue (BAT). Despite the controversy surrounding the importance of BAT in the control of body weight in adult humans, BAT size has been found to correlate negatively with body mass index and thus central regulators of BAT thermogenesis may be potential targets for anti-obesity drugs. A number of reports suggest that leptin, a pleiotropic adipocyte-derived hormone, may regulate body weight, in part, by central thermoregulatory mechanisms. Indeed, leptin-responsive neurons in the dorsomedial hypothalamus (DMH) have been shown to recapitulate such central thermoregulatory pathways. Accordingly, we hypothesize that DMH leptin receptor (LepRb) expressing neurons regulate energy expenditure via BAT NST and represent an indirect means of body weight control. Here, the proposed studies will examine LepRb expressing neurons in the DMH of mice using molecular biological state-of-the-art tools that have hitherto not been used in the thermoregulation research field, including pharmacogenetics and optogenetics. The objective of these studies is to advance our understanding of NST and facilitate the identification of novel, druggable targets for the treatment of obesity. This objective will be accomplished by modulating the neuronal activity of DMH LepRb expressing neurons in vivo to study their effect on body weight/composition, energy expenditure, and body temperature during nutritional challenges in two aims. SPECIFIC AIM I will examine the relationship between DMH leptinergic neuronal activity and body weight/composition by using pharmacogenetic designer receptors exclusively activated by designer drugs (DREADD) technology. SPECIFIC AIM II will investigate if DMH LepRb expressing neurons integrate other nutrient signals that also regulate energy expenditure by using optogenetic technology.