NNAT in metabolic regulation

项目概要/摘要 肥胖与严重的医疗并发症有关，导致医疗保健比例不断上升 在美国的费用。虽然市场上大多数抗肥胖药物通过抑制食欲起作用， 通过刺激产热来增加能量消耗是另一种策略。人和老鼠都 具有组成型活性和诱导性产热脂肪，通常称为棕色和米色脂肪。同时 解偶联蛋白 1 (UCP1) 长期以来被认为对于脂肪的非颤抖产热至关重要 组织，最近的研究已经证明了 UCP1 独立的产热机制，并且它们可能是 在米色脂肪中尤其重要。我们最近鉴定了内质网（ER）膜蛋白 Nnat 作为脂肪细胞生热作用的新型抑制剂，并已表明其对生热作用的影响是 独立于 UCP1。我们假设脂肪组织中的 Nnat 在控制生热作用中发挥关键作用 和葡萄糖稳态。在目标 1 中，我们将通过以下方式来描述全身能量代谢的调节： 脂肪组织 Nnat。在目标 2 中，我们将研究 Nnat 作用的机制基础并检验其 与 ER 钙泵 SERCA 的相互作用以及 Nnat 影响生热作用的其他可能方式。 这些研究将为脂肪组织生热的控制提供新的见解，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.