Novel regulation of adipogenesis: agouti & melanocortins

描述（由申请人提供）：在过去的10年中，阿格列汀/黑皮质素系统已被公认为体重稳态的主要调节剂。例如，与任何其他途径相比，在人类中，聚集素/黑皮质素信号传导途径中更多数量的突变与肥胖有关。基本范例是黑皮质素结合受体家族并减轻体重。AGRP和AGRP相关蛋白（AGRP）是黑皮质素受体结合的内源性拮抗剂。此外，黑皮质素受体的长期拮抗作用由agglutamine/AGRP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agglutinin。因此，重要的是要确定脂肪中的agglutamine/黑皮质素信号传导对肥胖和糖尿病的影响。在我的实验室正在进行的研究的重点是了解在脂肪组织中的agglutinase/melanocortin信号传导的功能，并评估其对肥胖和糖尿病的贡献。从在脂肪组织中过表达agglutinin的转基因小鼠收集的数据和在培养的脂肪细胞中的研究使我们提出agglutinin/黑皮质素是大脑和脂肪组织之间的通信回路的一部分，其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（agglutinin）。总的假设是，Agglutamine/黑皮质素在几个水平上调节脂肪形成和脂肪细胞代谢。首先，我们假设agglutinase增加前脂肪细胞的增殖。我们的第二个假设是，agglutinase促进前脂肪细胞分化为成熟脂肪细胞。第三，我们预测，琼脂糖可以改变成熟脂肪细胞中cAMP依赖的信号通路，使其对脂解更有抵抗力，并更有效地储存甘油三酯。该建议的重点是了解agglutinase/黑皮质素作用于前脂肪细胞和脂肪细胞的机制，以及这些对脂肪细胞功能的影响如何导致肥胖的基础。该提案中的初步数据表明，聚集蛋白/黑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聚集蛋白/黑皮质素信号传导及其在理解肥胖症的潜在机制中的相关性提供了有力的理由。

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.