1697-P: NFIA Differentially Regulates Adipogenesis and Myogenesis through Distinct Molecular Pathways to Ensure Adipocyte Differentiation

Abstract

Brown and beige fat dissipate chemical energy in the form of heat through uncoupling protein-1 (Ucp1) on the mitochondrial inner membrane as well as through the other pathways, while white fat generally stores energy in the form of lipid. Stimulating development and/or function of brown fat is highly anticipated as a novel strategy for the treatment of obesity and its complications including type 2 diabetes. Previously, we identified a transcription factor nuclear factor I-A (NFIA) as a crucial regulator of brown fat. NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma (peroxisome proliferator-activated receptor gamma—a master transcription factor of adipogenesis), to control the brown fat gene program. Here we show that the C-terminal 17 amino acid residues of NFIA (which we call pro#3 domain) are required for the transcriptional activity of NFIA. Full-length NFIA—but not deletion mutant lacking pro#3 domain—rescued impaired Pparg expression and adipogenesis in NFIA-knockout cells. However, the deletion mutant still binds to Myod1 enhancer to represses Myod1 expression via competition with KLF5 in terms of enhancer binding, leading to suppression of myogenic gene program. Therefore, the negative effect of NFIA on the myogenic gene program is, at least partly, independent of the positive effect on Pparg expression and its downstream adipogenic gene program. Overall, our results uncover multiple ways of action of NFIA to ensure optimal regulation of brown adipocyte differentiation. Disclosure Y. Hiraike: Research Support; Self; Daiichi Sankyo, Daiichi Sankyo, Novo Nordisk Inc., Novo Nordisk Inc. H. Waki: Research Support; Self; Astellas Pharma Inc., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Takeda Science Foundation, The Cell Science Research Foundation. Speaker’s Bureau; Self; AstraZeneca K.K., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Kyowa Hakko Kirin Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K. K. Miyake: Research Support; Self; NTT DOCOMO, INC. M. Oguchi: None. T. Yamauchi: Research Support; Self; AeroSwitch, Asahi Mutual Life Insurance Company, Astellas Pharma Inc., AstraZeneca K.K., Boehringer Ingelheim International GmbH, Daiichi Sankyo Company, Limited, Kowa Pharmaceutical company,limited., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Corporation Life Sciences Limited, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., NTT Docomo Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, TOSOH CORPORATION. Other Relationship; Self; Covidien Japan Inc. (Medtronic Japan Co., Ltd.), Eli Lilly Japan K.K., Johnson & Johnson, Kissei Pharmaceutical Co., Ltd. T. Kadowaki: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, MSD Corporation, Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; Abbott, Astellas Pharma Inc., AstraZeneca K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Cosmic Corporation, Daiichi Sankyo, Eli Lilly Japan K.K., FUJIFILM, Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Medscape Education, Medtronic, Mitsubishi Tanabe Pharma Corporation, MSD Corporation, NIPRO Medical Corporation, Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Asahi Mutual Life Insurance.