Novel regulation of adipogenesis: agouti & melanocortins

描述(由申请人提供)：在过去的10年里，刺鼠/黑素皮质素系统已被公认为体重稳态的主要调节因素。例如，与任何其他途径相比，刺鼠/黑素皮质素信号通路中更多的突变与人类肥胖有关。其基本模式是黑素皮质素与一系列受体结合，减轻体重。刺鼠和刺鼠相关蛋白(AGRP)是黑素皮质素受体结合的内源性拮抗剂。此外，刺参/AGRP对黑素皮质素受体的长期拮抗会导致肥胖。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刺参。因此，确定脂肪中刺鼠皮质素/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的重点是了解刺鼠/黑素皮质素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。从转基因小鼠收集的数据在脂肪组织中过表达刺激肽，并对培养的脂肪细胞进行的研究使我们提出，刺鼠皮质素/黑素皮质素是大脑和脂肪组织之间通信电路的一部分，该电路传递中央介导的信号(ACTH和α-MSH)并调节脂肪细胞对这些信号的反应(刺鼠)。总的假设是，Agti/黑素皮质素在多个水平上调节脂肪生成和脂肪细胞代谢。首先，我们假设刺参能促进前脂肪细胞的增殖。我们的第二个假设是，刺鼠可以促进前脂肪细胞向成熟脂肪细胞分化。第三，我们预测，刺参可以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，并能更有效地储存甘油三酯。这项建议的重点是了解刺参/黑素皮质素对前脂肪细胞和脂肪细胞的作用机制，以及这些对脂肪细胞功能的影响如何导致肥胖的基础。这项研究的初步数据表明，刺鼠/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刺鼠/黑素皮质素信号及其与理解肥胖的潜在机制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.