Oral Presentation ANZOS-OSSANZ-AOCO Joint Annual Scientific Meeting 2017

NFIA controls the brown fat gene program by co-localizing with pparγ at cell-type-specific enhancers (#33)

Yuta Hiraike 1 , Hironori Waki 1 , Shuichi Tsutsumi 2 , Hiroyuki Aburatani 2 , Toshimasa Yamauchi 1 , Takashi Kadowaki 1
  1. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
  2. Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan

Brown fat dissipates energy in the form of heat by means of the uncoupling protein-1 (UCP1) on the mitochondrial inner membrane. In humans, brown fat activity is inversely correlated with body mass index. And several pilot studies have shown that therapeutic interventions such as chronic cold exposure successfully recruit human brown fat and increase systemic energy expenditure. Therefore, stimulating development and/or function of brown fat would be a novel strategy for the treatment of obesity and its complications. However, global landscape of brown fat development is not entirely understood. Here, we identified nuclear factor I-A (NFIA) as a novel transcriptional regulator of brown fat. The binding motif for Nuclear factor I (NFI) transcription factor is enriched within brown-fat-specific open chromatin regions. Of the four isoforms of NFI family, NFIA is highly expressed in brown fat compared to white fat or muscle. Introduction of NFIA into myoblasts results in lipid accumulation, activation of the brown fat gene program and suppression of muscle gene program. Conversely, the brown fat of NFIA knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. Moreover, human perirenal brown fat of patients with pheochromocytoma show concurrent increase in NFIA and UCP1 expression. Mechanistically, NFIA selectively co-localize with PPARγ at the brown-fat-specific enhancers, and co-localization of NFIA facilitates the binding of PPARγ, leading to increased chromatin accessibility and active transcription. Collectively, these results indicate that NFIA is a novel key transcription factor that co-localizes with PPARγ and activates the brown fat gene program.