Novel regulation of adipogenesis: agouti & melanocortins

描述（由申请人提供）：在过去的10年里，针刺/黑素皮质素系统被认为是体重稳态的主要调节者。例如，agouti/黑素皮质素信号通路中与人类肥胖相关的突变比任何其他途径都要多。基本的范例是黑素皮质素与受体家族结合并减轻体重。Agouti和Agouti相关蛋白（AGRP）是黑素皮素受体结合的内源性拮抗剂。此外，agouti/AGRP对黑素皮质素受体的慢性拮抗导致肥胖。我们的初步数据清楚地表明，人类在脂肪组织中表达和调节agouti。因此，确定脂肪中agouti/黑素皮质素信号对肥胖和糖尿病的影响是很重要的。我的实验室正在进行的研究重点是了解agouti/melanocortin信号在脂肪组织中的功能，并评估其在肥胖和糖尿病中的作用。从脂肪组织中过表达agouti的转基因小鼠和对培养脂肪细胞的研究中收集的数据使我们提出agouti/黑素皮质素是大脑和脂肪组织之间通信回路的一部分，该回路传递中枢介导的信号（ACTH和α - msh）并调节脂肪细胞对这些信号的反应（agouti）。总的假设是Agouti/黑素皮质素在多个水平上调节脂肪形成和脂肪细胞代谢。首先，我们假设阿古提增加了前脂肪细胞的增殖。我们的第二个假设是，刺古提促进了前脂肪细胞向成熟脂肪细胞的分化。第三，我们预测刺蒺藜会改变成熟脂肪细胞中camp依赖的信号通路，使其更能抵抗脂肪分解，并更有效地储存甘油三酯。本提案的重点是了解agouti/黑素皮质素作用于前脂肪细胞和脂肪细胞的机制，以及这些作用于脂肪细胞功能如何导致肥胖的基础。本提案的初步数据表明，针刺/黑素皮质素系统可能是脂肪细胞功能的主要调节因子之一，就像它是体重稳态的主要调节因子一样，这为研究脂肪组织中的针刺/黑素皮质素信号传导及其与理解肥胖潜在机制的相关性提供了强有力的证据。

DESCRIPTION (provided by applicant): Over the past 10 years the agouti/melanocortin system has become recognized as a major regulator of bodyweight homeostasis. For example, a greater number of mutations in the agouti/melanocortin signaling pathway are linked to obesity in humans than any other pathway. The basic paradigm is that melanocortins bind to a family of receptors and reduce bodyweight. Agouti and agouti related protein (AGRP) are endogenous antagonists of melanocortin receptor binding. Moreover, the chronic antagonism of melanocortin receptors by agouti/AGRP leads to obesity. Our preliminary data clearly demonstrate that humans express and regulate agouti in adipose tissue. Therefore, it is important to determine the impact of agouti/melanocortin signaling in fat on obesity and diabetes. The focus of ongoing studies in my laboratory is to understand the function of agouti/melanocortin signaling in adipose tissue and evaluate its contribution to obesity and diabetes. Data collected from transgenic mice that overexpress agouti in adipose tissue and studies in cultured adipocytes have led us to propose that agouti/melanocortins are part of a communication circuit between the brain and adipose tissue which conveys centrally-mediated signals (ACTH and alpha-MSH) and modulates adipocytes responsiveness to these signals (agouti). The overall hypothesis is that Agouti/melanocortins regulate adipogenesis and adipocyte metabolism at several levels. First, we hypothesize that agouti increases the proliferation of preadipocytes. Our second hypothesis is that agouti promotes the differentiation of preadipocytes into mature adipocytes. Third, we predict that agouti alters cAMP-dependent signaling pathways in the mature adipocyte such that it is more resistant to lipolysis and more efficient at storing triglycerides. The focus of this proposal is to understand both the mechanisms of agouti/melanocortin action on preadipocytes and adipocytes and the basis for how these effects on adipocyte function contribute to obesity. The preliminary data in this proposal demonstrate that the agouti/melanocortin system is potentially one of the major regulators of adipocyte function, just as it is a major regulator of bodyweight homeostasis, This makes a strong case for studying agouti/melanocortin signaling in adipose tissue and its relevance in understanding the underlying mechanisms of obesity.