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

通过 DMH 进行体温调节瘦素作用在体重控制中的作用

• 批准号: 8457725
• 负责人: Kavon Paul Rezai-Zadeh
• 金额: $ 5.39万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457725
• 关键词: ATP Synthesis Pathway; Acute; Adipocytes; Adipose tissue; Adult; Agonist; American; Anti-Obesity Agents; Area; Biological; Blood Glucose; Body Temperature; Body Weight; Body Weight decreased; Body mass index; Brain; Brown Fat; Burn injury; Cell physiology; Cells; Cessation of life; Comorbidity; Designer Drugs; Diet; Dorsal; Eating; Energy Intake; Energy Metabolism; Epidemic; Event; Exercise; Fatty Acids; Fatty acid glycerol esters; Frequencies; Health system; Heating; Hormones; Human; Hyperlipidemia; Hyperphagia; Hypertension; Hypothalamic structure; Individual; Injection of therapeutic agent; Intervention; Investigation; Kinetics; Leptin; Liver; Mammals; Mediator of activation protein; Melanocortin 4 Receptor; Metabolic syndrome; Mitochondria; Molecular; Monitor; Mus; Muscle; Neuraxis; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional; Obesity; Pathway interactions; Peripheral; Pharmacogenetics; Physical activity; Physiologic Thermoregulation; Physiological; Play; Polypeptide Hormones; Population; Prevalence; Process; Public Health; Publications; Regimen; Reporter; Reporting; Research; Respiration; Risk; Role; Signal Transduction; Site; Source; Technology; Temperature; Therapeutic; Thermogenesis; Thyroid Hormones; Tissues; United States; Weight maintenance regimen; cohort; cost; diet and exercise; feeding; improved; in vivo; leptin receptor; novel; obesity treatment; optogenetics; receptor; success; tool

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.

描述（由申请人提供）：肥胖症在世界范围内已达到流行病的程度，特别是在美国等繁荣国家。体重指数 (BMI) > 30 kg/m2 在临床上将个体定义为肥胖，并显着增加个体患其他合并症的风险，这些合并症包括代谢综合征的“致命四重奏”，包括 II 型糖尿病、高血压和高脂血症。在缺乏有效的抑制肥胖的干预策略的情况下，促进非颤抖产热（NST）已重新成为一种潜在可行的方法。 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 在控制成年人体重方面的重要性存在争议，但已发现 BAT 大小与体重指数呈负相关，因此 BAT 生热作用的中枢调节因子可能是抗肥胖药物的潜在目标。许多报告表明，瘦素（一种多效性脂肪细胞衍生激素）可能部分通过中枢体温调节机制调节体重。事实上，下丘脑背内侧 (DMH) 中的瘦素反应神经元已被证明能够重现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，拟议的研究将使用分子生物学最先进的工具来检查小鼠 DMH 中表达 LepRb 的神经元，这些工具迄今为止尚未用于温度调节研究领域，包括药物遗传学和光遗传学。这些研究的目的是增进我们对 NST 的理解并促进识别 治疗肥胖症的新型药物靶标。该目标将通过调节体内表达 DMH LepRb 的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/成分、能量消耗和体温的影响，以实现两个目标。具体目标 我将通过使用专门由设计药物 (DREADD) 技术激活的药物遗传学设计受体来研究 DMH 瘦素能神经元活动与体重/成分之间的关​​系。 SPECIFIC AIM II 将研究表达 DMH LepRb 的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。 公共卫生相关性：当前的肥胖治疗尚未成功，肥胖人数持续急剧上升就证明了这一点。越来越明显的是，需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维持体温，这一过程燃烧白色脂肪作为燃料来源。瘦素是一种由脂肪细胞产生的激素，有人认为在这一过程中发挥作用。该提案研究了瘦素如何导致大脑刺激棕色脂肪细胞产生热量，以及如何利用这一过程来促进减肥。