NFIA Colocalizes with PPARgamma and Activates the Cell-Type–Specific Enhancers to Control the Brown Fat Gene Program

Abstract

Brown fat dissipates energy as heat by means of the uncoupling protein-1 (UCP1) on the mitochondrial inner membrane. Brown fat activity is inversely correlated with body mass index in humans, and pilot studies have shown that 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. Here, we identified nuclear factor I-A (NFIA) as a transcriptional regulator of brown fat by a genome-wide open chromatin analysis of murine brown and white fat followed by motif analysis of the brown-fat-specific open chromatin regions. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. In human brown fat, expression of NFIA and the brown-fat-specific genes including UCP1 is positively correlated. Mechanistically, NFIA co-localizes with the master transcriptional regulator of adipogenesis, PPARgamma, selectively at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARgamma, leading to increased chromatin accessibility and active transcription. Most recently, we performed mass spectrometry analysis of NFIA protein complex to identify and characterize the crucial partner of NFIA-dependent brown-fat-specific chromatin regulation. Collectively, these results indicate that NFIA is a key transcription factor that activates the cell-type-specific enhancers and facilitates the binding of PPARgamma for controlling the brown fat gene program. Disclosure Y. Hiraike: Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S, Mitsubishi Tanabe Pharma Corporation. H. Waki: Research Support; Self; MSD K.K., Novartis Pharma K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi K.K., Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Takeda PHarmaceutical Co., Ltd.. S. Tsutsumi: None. H. Aburatani: None. T. Yamauchi: Research Support; Self; Novo Nordisk Inc., Daiichi Sankyo Company, Limited, Sanofi, Takeda, Tanabe-Mitsubishi. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.