BAT-mediated inter-organ communication in energy homeostasis

 描述(申请人提供)：糖尿病是美国和世界范围内最严重和最紧迫的健康问题之一。由于外周器官如骨骼肌的胰岛素抵抗先于2型糖尿病的发病，因此更好地了解外周胰岛素抵抗的机制对于2型糖尿病的治疗至关重要。棕色脂肪组织(BAT)以热量的形式消耗能量，在肥胖条件下显著改善全身和外周血糖稳态。虽然传统的共识是，这种改善是BAT抗肥胖作用的新陈代谢结果，但新的证据表明，BAT可能通过分泌直接作用于周围组织的脂肪因子来直接控制血糖稳态。我们的长期目标是了解蝙蝠和代谢器官(如骨骼肌)通过分泌分子相互沟通以调节全身能量代谢的机制。我们最近从蝙蝠身上发现了一种以前未被赏识的分泌分子，博拉家族成员3(Bola3)。我们的初步数据表明，Bola3作用于骨骼肌，促进葡萄糖的摄取和丙酮酸脱氢酶(PDH)的活性，丙酮酸脱氢酶是葡萄糖氧化的关键代谢调节因子。因此，我们目前的目标是验证这一假设，即Bola3是一种蝙蝠来源的脂肪因子，它通过激活骨骼肌中的PDH来调节葡萄糖稳态和胰岛素敏感性。为了验证这一假说，我们将追求以下具体目标：在目标1中，我们将测试蝙蝠来源的Bola3在体内维持能量和葡萄糖动态平衡的遗传需求。我们还将通过检查Bola3在体内改善外周胰岛素敏感性的程度来评估Bola3的治疗潜力。在目标2中，我们将进行一系列的生化分析，以研究Bola3控制骨骼肌糖代谢和PDH活性的分子机制。这些研究的预期结果是描述一种全新的蝙蝠来源的分泌因子，它调节全身和外周葡萄糖的动态平衡。我们的发现将产生重大影响，因为这项研究将提供一个新的实体，可以改善全身葡萄糖稳态和逆转骨骼肌中的胰岛素抵抗。我们的研究还将发展创新的概念，即BAT不仅是一个简单的生热器官，还可以作为一个内分泌器官来控制血糖稳态和外周胰岛素敏感性。

 DESCRIPTION (provided by applicant): Diabetes is one of the most serious and urgent health concerns in the U.S. and worldwide. Because insulin resistance in peripheral organs, such as skeletal muscle, precedes the onset of type 2 diabetes, it is crucial to better understand the mechanisms of peripheral insulin resistance for the treatment of type 2 diabetes. Brown adipose tissue (BAT), which dissipates energy in the form of heat, significantly contributes to an improvement in systemic and peripheral glucose homeostasis under obesity conditions. While the conventional consensus has been that such improvement is a metabolic consequence of BAT's anti-obesity effects, new evidence indicates that BAT may directly control glucose homeostasis by secreting adipokines that act directly on peripheral tissues. Our long-term goal is to understand the mechanisms by which BAT and metabolic organs, such as skeletal muscle, communicate with each other to regulate whole-body energy metabolism through secreted molecules. We recently identified a previously unappreciated secreted molecule from BAT, BolA Family Member 3 (Bola3). Our preliminary data indicate that Bola3 acts on skeletal muscle to enhance glucose uptake and the enzymatic activity of pyruvate dehydrogenase (PDH), a key metabolic regulator of glucose oxidation. Hence, our current objective is to test the hypothesis that Bola3 is a BAT-derived adipokine that regulates glucose homeostasis and insulin sensitivity by PDH activation in skeletal muscle. To test this hypothesis, we will pursue the following specific aims: In aim 1, we will test the genetic requirement of BAT-derived Bola3 for maintaining energy and glucose homeostasis in vivo. We will also assess the therapeutic potential of Bola3 by examining the extent to which Bola3 improves peripheral insulin sensitivity in vivo. In aim 2, we will conduct a series of biochemical analyses to investigate the molecular mechanisms by which Bola3 controls glucose metabolism and PDH activity in skeletal muscle. The expected outcome of these studies is to characterize a completely novel BAT-derived secretory factor that regulates systemic and peripheral glucose homeostasis. Our findings will have a significant impact, because this study will provide a new entity that can improve systemic glucose homeostasis and reverse insulin resistance in skeletal muscle. Our study will also develop the innovative concept that BAT is not simply a heat-generating organ, but can also function as an endocrine organ to control glucose homeostasis and peripheral insulin sensitivity.