Regulation of Adipose Tissue Metabolism by Central Insulin and Leptin

中枢胰岛素和瘦素对脂肪组织代谢的调节

基本信息

批准号：
8583420
负责人：
CHRISTOPH BUETTNER
金额：
$ 0.15万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-28 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8583420
关键词：
Acute Adipocytes Adipose tissue Adult Aging Area Autonomic nervous system Biological Preservation Brain Brown Fat Caloric Restriction Cardiovascular Diseases Cells Comorbidity Conscious Development Diabetes Mellitus Diet Doctor of Philosophy Dyslipidemias Eating Endocannabinoids Endocrine Glands Failure Fasting Fatty Acids Fatty acid glycerol esters Genetic Glucose Goals Health Homeostasis Hormones Human Hyperinsulinism Hypothalamic structure In Vitro Inflammatory Infusion procedures Insulin Insulin Receptor Insulin Resistance Isotopes Lead Leptin Leptin resistance Lipids Lipodystrophy Lipolysis Mediating Metabolic syndrome Metabolism Molecular Molecular Genetics Mus Neurons Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Organ PIK3CG gene Pathway interactions Peripheral Physiological Play Rattus Regulation Regulatory Pathway Risk Factors Rodent Model Role Signal Pathway Signal Transduction Techniques Testing Third ventricle structure Tissues Tracer Ventricular Visceral Work adipokines adiponectin base cytokine glucose metabolism in vivo insulin signaling leptin receptor lipid biosynthesis lipid metabolism mind control mouse model nerve supply novel nutrient metabolism prevent protein expression transdifferentiation uptake

项目摘要

DESCRIPTION (provided by applicant): Visceral adiposity is a major risk factor for the development of insulin resistance, type 2. diabetes and its co-morbidities of dyslipidemia and cardiovascular disease. Adipose tissue has been recognized to be an important endocrine organ that regulates energy homeostasis, glucose and lipid metabolism via adipokines like leptin and adiponectin, fatty acid release and possibly neuronal afferens. Insulin and leptin are two of the major adiposity hormones that have been shown to regulate food intake and glucose fluxes to a large extend via central, i.e. brain signaling. While leptin decreases adiposity, insulin increases lipid storage in adipose tissue chiefly by suppressing lipolysis. The inhibition of lipolysis by insulin is believed to be mediated exclusively by insulin signaling in adipocytes. The brain control of adipose tissue metabolism via the autonomic nervous system is poorly understood. Previous work from our lab has demonstrated that leptin suppresses lipogenesis and induces lipolysis in adipose tissue via the medio-basal hypothalamus (MBH) and requires intact sympathetic innervation of adipose tissue. Since insulin exerts the opposite physiological effects on adipose metabolism then insulin, we speculated that part of insulins prolipogenic and antilipolytic effects are mediated by brain insulin signaling. Indeed, we have made the novel observation that insulin infused into the third ventricle or the MBH potently suppresses whole body and adipose tissue lipolysis and induces adipose tissue lipogenic protein expression independent of changes in circulating insulin and glucose levels or food intake. Thus, the central hypothesis of our proposal is that leptin and insulin exert opposing effects on visceral adipose tissue metabolism. We wish to characterize the central and peripheral pathways that participate in the brain control of adipose tissue metabolism and lipid fluxes in physiological and pathophysiological (dietary, inflammatory and genetic insulin resistance) contexts to understand if impaired brain control of adipose tissue metabolism contributes to the unrestrained lipolysis in the insulin resistant state. These studies should advance our understanding of how the brain controls WAT metabolism and adiposity independent of food intake by regulating nutrient partitioning.

描述（由申请人提供）：内脏肥胖是发生胰岛素抵抗、2 型糖尿病及其血脂异常和心血管疾病的并发症的主要危险因素。脂肪组织已被认为是重要的内分泌器官，它通过瘦素和脂联素等脂肪因子、脂肪酸释放以及可能的神经元传入来调节能量稳态、葡萄糖和脂质代谢。胰岛素和瘦素是两种主要的肥胖激素，已被证明可以通过中枢（即大脑）信号在很大程度上调节食物摄入和葡萄糖通量。瘦素可以减少肥胖，而胰岛素主要通过抑制脂肪分解来增加脂肪组织中的脂质储存。据信胰岛素对脂肪分解的抑制仅由脂肪细胞中的胰岛素信号介导。人们对大脑通过自主神经系统控制脂肪组织代谢知之甚少。我们实验室之前的工作表明，瘦素通过中基底下丘脑 (MBH) 抑制脂肪生成并诱导脂肪组织中的脂肪分解，并且需要脂肪组织完整的交感神经支配。由于胰岛素对脂肪代谢产生与胰岛素相反的生理作用，因此我们推测胰岛素的部分促脂作用和抗脂解作用是由脑胰岛素信号传导介导的。事实上，我们进行了新的观察，即注入第三脑室或 MBH 的胰岛素可有效抑制全身和脂肪组织的脂肪分解，并诱导脂肪组织脂肪生成蛋白的表达，而与循环胰岛素和葡萄糖水平或食物摄入的变化无关。因此，我们建议的中心假设是瘦素和胰岛素对内脏脂肪组织代谢产生相反的影响。我们希望描述在生理和病理生理（饮食、炎症和遗传性胰岛素抵抗）背景下参与大脑控制脂肪组织代谢和脂质流动的中枢和外周途径，以了解大脑对脂肪组织代谢的控制受损是否会导致不受限制的脂肪组织代谢。胰岛素抵抗状态下的脂肪分解。这些研究应该加深我们对大脑如何通过调节营养分配来独立于食物摄入来控制 WAT 代谢和肥胖的理解。