Leptin Production and Action in Adipocytes

脂肪细胞中瘦素的产生和作用

• 批准号: 6682096
• 负责人: YIYING ZHANG
• 金额: $ 39.39万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6682096
• 关键词: adipocytes; age difference; athymic mouse; bioenergetics; biological signal transduction; cell biology; cell morphology; cell population study; gene environment interaction; gene expression; genetically modified animals; hormone regulation /control mechanism; insulin sensitivity /resistance; laboratory rat; leptin; metabolism; molecular genetics; nutrient intake activity; nutrition related tag; peptide hormone biosynthesis; pharmacology; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): Leptin plays a critical role in regulating systemic energy balance. This hormone's role in signaling the status of peripheral fat stores to the central nervous system, and in regulating energy intake and expenditure are well documented. The goal of this proposal is to address two less-well defined, but critically related, aspects of the biology of leptin. Specific Aim I is to investigate the molecular mechanisms responsible for the close correlation between leptin gene expression, adipocyte size and the metabolic status of adipocytes. Specific Aim II is to investigate the long-term effects of direct leptin action on metabolism and gene expression in adipocytes, and the contribution of direct leptin action in adipocytes to systemic energy homeostasis. In Specific Aim I, the hypothesis being tested is that the metabolic status of adipocytes is a primary determinant of leptin gene expression, a unifying mechanism responsible for signaling adipocyte size in fed states (long term energy balance) and acute caloric deficit in fasting states (short-term energy balance). The metabolic status of adipocytes will be manipulated using nutritional, pharmacological and molecular genetic tools, and the effects of such manipulations on relationships of leptin gene expression with the metabolic status and size of adipocytes will be determined. Metabolic intermediates responsible for regulating leptin gene expression to reflect changes in adipocyte size and acute systemic caloric balance will be identified. In Specific Aim II, the hypothesis being tested is that direct leptin actions in adipocytes play a significant role in regulating local adipocyte metabolism and gene expression. Such local action of leptin may affect body fat distribution and depot-specific differences in adipocyte functions. A preadipocyte implantation system will be used to study direct leptin actions on local adipocyte functions in vivo. Adenovirus-mediated gene transfer will be used to modify leptin receptor function or the rate of leptin production in cultured preadipocytes, which will then be implanted in athymic nude mice. The effects of these modifications on adipocyte functions (metabolism and expression of secreted proteins) in the mature adipocytes derived from these implanted preadipocytes will be determined. The effects of direct leptin actions on the adipocyte functions in anatomically distinct fat depots will also be investigated in tissue-specific transgenic mouse models. A better understanding of the regulation of leptin production in adipocytes in response to changes in systemic energy balance will provide a basis for preventing the decrease of leptin production induced by dieting or weight loss, thus blocking a feedback regulatory mechanism that interferes with success in clinical weight loss efforts. The work on the role of direct leptin actions in regulating local adipocyte functions will provide insights into the mechanisms and molecules involved in the regulation of body fat distribution and development of depot-specific differences in adipocyte metabolism, and provide a basis for rationalizing the prevention and treatment of abdominal obesity and its metabolic co-morbidities, such as insulin resistance, dyslipidemia, hypertension, diabetes and cardiovascular diseases.

描述（由申请人提供）：瘦素在调节系统能量平衡中发挥着关键作用。这种激素在向中枢神经系统发出外周脂肪储存状态信号以及调节能量摄入和消耗方面的作用已有详细记录。该提案的目标是解决瘦素生物学的两个不太明确但密切相关的方面。具体目标一是研究瘦素基因表达、脂肪细胞大小和脂肪细胞代谢状态之间密切相关的分子机制。具体目标二是研究瘦素直接作用对脂肪细胞代谢和基因表达的长期影响，以及脂肪细胞直接瘦素作用对全身能量稳态的贡献。在特定目标 I 中，正在测试的假设是，脂肪细胞的代谢状态是瘦素基因表达的主要决定因素，瘦素基因表达是负责在进食状态（长期能量平衡）下发出脂肪细胞大小信号和在禁食状态下（短期能量平衡）下发生急性热量赤字的统一机制。将使用营养、药理学和分子遗传学工具来操纵脂肪细胞的代谢状态，并且将确定这种操纵对瘦素基因表达与脂肪细胞的代谢状态和大小的关系的影响。将鉴定负责调节瘦素基因表达以反映脂肪细胞大小和急性全身热量平衡变化的代谢中间体。在特定目标 II 中，正在测试的假设是脂肪细胞中瘦素的直接作用在调节局部脂肪细胞代谢和基因表达中发挥着重要作用。瘦素的这种局部作用可能会影响身体脂肪分布和脂肪细胞功能的特异性差异。前脂肪细胞植入系统将用于研究瘦素对体内局部脂肪细胞功能的直接作用。腺病毒介导的基因转移将用于改变培养的前脂肪细胞中的瘦素受体功能或瘦素产生率，然后将其植入无胸腺裸鼠中。将确定这些修饰对源自这些植入的前脂肪细胞的成熟脂肪细胞中的脂肪细胞功能（分泌蛋白的代谢和表达）的影响。瘦素的直接作用对解剖学上不同的脂肪库中脂肪细胞功能的影响也将在组织特异性转基因小鼠模型中进行研究。更好地了解脂肪细胞中瘦素生成对全身能量平衡变化的调节，将为防止节食或减肥引起的瘦素生成减少提供基础，从而阻断干扰临床减肥努力成功的反馈调节机制。关于瘦素直接作用在调节局部脂肪细胞功能中的作用的研究将深入了解参与调节身体脂肪分布和脂肪细胞代谢中库特异性差异的发展的机制和分子，并为合理预防和治疗腹部肥胖及其代谢并发症（如胰岛素抵抗、血脂异常、 高血压、糖尿病和心血管疾病。