NNAT in metabolic regulation

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.