CNS EFFECTS OF ADIPOKINES ON METABOLISM

脂肪因子对代谢的中枢神经系统影响

• 批准号: 7215487
• 负责人: REXFORD S. AHIMA
• 金额: $ 30.81万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215487
• 关键词: adipocytes; adiponectin; bioenergetics; biological signal transduction; cell differentiation; central nervous system; chemical kinetics; developmental genetics; genetically modified animals; glucose metabolism; histogenesis; hormone regulation /control mechanism; hypothalamus; immunocytochemistry; in situ hybridization; laboratory mouse; obesity; peptide hormone; radiotracer

Obesity has reached epidemic proportions and poses serious public health challenges, in particular type 2 diabetes, cardiovascular disease, sleep apnea, osteoarthritis and cancer. Adipocyte hormones may provide key insights into the pathogenesis of obesity-related diseases. Leptin and adiponectin stimulate fatty acid oxidation, decrease lipid levels and increase insulin sensitivity. In contrast, resistin decreases insulin sensitivity, and increases glucose and lipids. Leptin acts in the CMS to suppress appetite and increase energy expenditure, but also has direct effects on peripheral tissues. Adiponectin and resistin have direct actions on liver and muscle, but recent observations suggest that these adipokines also have central effects. We hypothesize that the divergent effects of these adipocytes on metabolism are mediated, at least in part, through distinct neuronal targets and signaling pathways in the hypothalamus. Specific Aim 1 will compare the effects of CMS administration of leptin, adiponectin and resistin on energy and glucose metabolism. We will examine the regulation of peripheral glucose fluxes using insulin clamp and radioactive tracer kinetics. Based on our preliminary studies showing an attenuation of the CMS effects of leptin and adiponectin in agouti mice, we will determine whether the opposite effects of leptin/adiponectin versus resistin on glucose levels is mediated through melanocortin (MC)4 receptor signaling. Specific Aim 2 will determine the sites of action of these adipocyte hormones in the hypothalamus, using Fos immunohistochemistry and in situ hybridization. Finally, Specific Aim 3 will determine whether the opposing metabolic effects of leptin, adiponectin and resistin occur through AMP-kinase and SOCS-3 in the hypothalamus. We will test the hypothesis that central administration of resistin antagonizes the central effects of leptin and adiponectin on metabolism, through reciprocal regulation of AMPK, SOC-3, or both signaling pathways. Understanding the hypothalamic and signaling pathways that mediate the effects of leptin, adiponctin and resistin will provide novel insights into the pathophysiology of obesity and diabetes that will facilitate novel diagnostic and treatment strategies.

肥胖已达到流行病的程度，并构成严重的公共卫生挑战，特别是2型 糖尿病、心血管疾病、睡眠呼吸暂停、骨关节炎和癌症。脂肪细胞激素可以提供 肥胖相关疾病发病机制的关键见解。瘦素和脂联素刺激脂肪酸 氧化，降低脂质水平和增加胰岛素敏感性。与此相反， 敏感性，并增加葡萄糖和脂质。瘦素在CMS中起作用，抑制食欲， 能量消耗，而且对外周组织有直接影响。脂联素和脂联素具有直接的 脂肪因子对肝脏和肌肉有作用，但最近的观察表明这些脂肪因子也有中枢作用。 我们推测，这些脂肪细胞对代谢的不同影响至少部分是由， 通过下丘脑中不同的神经元靶点和信号通路。具体目标1将比较 瘦素、脂联素和谷氨酰胺对CMS能量和葡萄糖代谢的影响。我们 将使用胰岛素钳夹和放射性示踪动力学检查外周葡萄糖流量的调节。 基于我们的初步研究显示瘦素和脂联素在大鼠中的CMS效应减弱， 我们将确定瘦素/脂联素对葡萄糖的相反作用是否与瘦素/脂联素对葡萄糖的相反作用有关。 黑素皮质素（MC）4受体信号传导介导的。具体目标2将确定 这些脂肪细胞激素在下丘脑中的作用，使用Fos免疫组织化学和原位 杂交方法最后，具体目标3将确定瘦素的相反代谢作用， 脂联素和脂联素通过下丘脑中的AMP-激酶和SOCS-3产生。我们将测试 假设中枢给予Leptin拮抗了瘦素和脂联素的中枢作用， 通过AMPK、SOC-3或这两种信号传导途径的相互调节来调节代谢。了解 下丘脑和信号通路介导的影响，瘦素，脂联素和lipoprotein将提供 对肥胖和糖尿病的病理生理学的新见解，这将有助于新的诊断和治疗。 治疗策略。