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

描述（由申请人提供）：肥胖在世界各地已经达到流行病的程度，特别是在像美国这样的繁荣国家。具有> 30 kg/m2的身体质量指数（BMI）在临床上将个体定义为肥胖，并且显著增加该个体发展包括代谢综合征的“致命四重奏”（包括II型糖尿病、高血压和高脂血症）的其他共病的风险。在缺乏有效的干预策略来控制肥胖的情况下，促进非颤抖性产热（NST）已经重新成为一种潜在可行的方法。NST通过从外周组织，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，但已发现BAT大小与体重指数呈负相关，因此BAT产热的中枢调节剂可能是抗肥胖药物的潜在靶点。许多研究表明，瘦素，一种多效脂肪细胞衍生的激素，可能部分通过中枢体温调节机制调节体重。事实上，瘦素反应神经元的背内侧下丘脑（DMH）已被证明重演这样的中央温度调节途径。因此，我们假设DMH瘦素受体（LepRb）表达神经元通过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为止尚未用于体温调节研究领域（包括药物遗传学和光遗传学）的分子生物学最先进的工具，检查小鼠DMH中表达LepRb的神经元。这些研究的目的是加深我们对NST的认识， 治疗肥胖的新型药物靶点。这一目标将通过在体内调节表达DMH LepRb的神经元的神经元活性来实现，以研究它们在两个目标的营养挑战期间对体重/组成、能量消耗和体温的影响。具体目的我将使用药物遗传学设计受体专门激活的设计药物（DREADD）技术检查DMH瘦素能神经元活性和体重/组成之间的关系。SPECIFIC AIM II将研究DMH LepRb表达神经元是否整合其他营养信号，这些信号也通过使用光遗传学技术调节能量消耗。

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.