NNAT in metabolic regulation

项目总结/摘要 肥胖与严重的医疗并发症有关，并导致医疗保健的比例上升 在美国的成本。虽然市场上大多数减肥药都是通过抑制食欲来起作用的， 通过刺激产热来增加能量消耗是一种替代策略。人类和老鼠 具有组成性活性和诱导产热脂肪，通常称为棕色和米色脂肪。而 解偶联蛋白1（UCP 1）长期以来被认为是脂肪组织非颤抖性产热的必需蛋白。 组织，最近的研究表明，UCP 1独立的产热机制，他们可能是 尤其是米色脂肪。我们最近发现了内质网（ER）膜蛋白 NNAT作为一种新的脂肪细胞产热抑制剂， UCP 1独立。我们假设脂肪组织中的Nnat在控制产热中起关键作用 和葡萄糖稳态。在目标1中，我们将通过以下方式描述全身能量代谢的调节： 脂肪组织在目标2中，我们将研究Nnat作用的机制基础，并将研究其 与ER钙泵SERCA的相互作用以及Nnat可以影响产热的其他可能方式。 这些研究将对脂肪组织产热的控制产生新的见解，并可能导致 抗肥胖治疗的新策略。

PROJECT SUMMARY/ABSTRACT Obesity is associated with serious medical complications and responsible for a rising percentage of health care costs in the United States. While most anti-obesity drugs in the market work by suppressing appetite, increasing energy expenditure by stimulating thermogenesis is an alternative strategy. Humans and mice both possess constitutively active and inducible thermogenic fat, commonly called brown and beige fat. While Uncoupling Protein 1 (UCP1) has long been considered essential for non-shivering thermogenesis in adipose tissues, recent studies have demonstrated UCP1-independent thermogenic mechanisms, and they may be especially important in beige fat. We recently identified the endoplasmic reticulum (ER) membrane protein Nnat as a novel inhibitor of adipocyte thermogenesis and have shown that its effects on thermogenesis are UCP1-independent. We hypothesize that Nnat in adipose tissue plays a key role in controlling thermogenesis and glucose homeostasis. In Aim 1, we will characterize the regulation of systemic energy metabolism by adipose tissue Nnat. In Aim 2, we will investigate the mechanistic basis of Nnat action and will examine its interactions with the ER calcium pump SERCA and other possible ways that Nnat can impact thermogenesis. These studies will produce new insights into the control of adipose tissue thermogenesis and potentially lead to new strategies for anti-obesity therapy.