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

描述(申请人提供)：肥胖症已经在世界范围内流行，特别是在像美国这样的富裕国家。在临床上，体重指数(BMI)为30公斤/平方米的人被定义为肥胖，并显著增加该人患其他共病的风险，这些共病构成代谢综合征的“致命四重奏”，包括II型糖尿病、高血压和高脂血症。在缺乏遏制肥胖的有效干预策略的情况下，促进非颤抖生热(NST)已重新成为一种潜在的可行方法。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。尽管围绕蝙蝠在成人体重控制中的重要性存在争议，但已发现蝙蝠的大小与体重指数呈负相关，因此蝙蝠产热的中央调节器可能是减肥药物的潜在靶点。许多报告表明，瘦素是一种多效性脂肪细胞来源的激素，可能部分通过中枢体温调节机制来调节体重。事实上，下丘脑背内侧(DMH)中的瘦素反应神经元已被证明概括了这种中枢体温调节通路。因此，我们假设DMH瘦素受体(LepRb)表达的神经元通过BAT NST调节能量消耗，并代表一种间接的体重控制手段。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来检测小鼠DMH中LepRb表达的神经元。这些研究的目的是增进我们对NST的了解，便于识别NST 治疗肥胖的新的、可用药的靶点。这一目标将通过在体内调节DMH LepRb表达神经元的神经元活动来实现，以研究它们在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I将通过使用由设计药物(DREADD)独有激活的药物遗传设计受体(DREADD)技术来研究DMH瘦素能神经元活动与体重/成分之间的关系。特定的AIM II将研究DMH LepRb表达的神经元是否整合了其他营养信号，这些信号也通过光遗传技术调节能量消耗。 与公共健康相关：目前的肥胖治疗并不成功，肥胖率持续大幅上升就是明证。越来越明显的是，有必要更好地了解控制体重的机制。在人类和其他哺乳动物中，棕色脂肪细胞产生热量并保持体温，这是一个燃烧白色脂肪作为燃料的过程。瘦素是一种由脂肪细胞产生的激素，已被认为在这一过程中发挥了作用。这项提案调查了瘦素如何导致大脑刺激棕色脂肪细胞产生热量，以及这一过程如何用于促进减肥。

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. PUBLIC HEALTH RELEVANCE: Current obesity therapies have not been successful, demonstrated by the ongoing dramatic rise in obesity. It is becoming increasingly apparent that there is need for a better understanding of the mechanisms controlling body weight. In humans and other mammals, brown fat cells generate heat and maintain body temperature, a process which burns white fat as a fuel source. Leptin, a hormone produced by fat cells, has been suggested to play a role in this process. This proposal investigates how leptin causes the brain to stimulate heat production from brown fat cells and how this process can used to promote weight loss.