Nampt is the rate-limiting enzyme in salvage pathway in which NAD is mainly synthesized in mammalian cells. NAD plays very important role in various biological processes, such as energy production, energy consumption, aging, cell death, and DNA damage repair as a coenzyme of redox reactions or as a substrate of Sirtuins or Poly (ADP-ribose) polymerases. Besides, Nampt is highly expressed in mature adipocyte and secreted into extracellular. The extracellular Nampt is known to regulate systemic metabolic state. In short, Nampt works as a metabolic sensor and NAD integrates systemic metabolism. Recently, metabolism is thought to be closely related to cell differentiation. However, how NAD metabolism affects to adipogenesis remains unknown. In this study, we generated the adipose tissue specific Nampt knock out mice, Adiponectin-Cre Nampt flox/flox (KO) and conducted targeted-metabolomic analysis to investigate the metabolic effect, employing liquid-chromatograph mass spectrometry and gas-chromatograph mass spectrometry. Interestingly, KO showed resistant against diet-induced obesity (DIO), fed high fat high sucrose diet. Body weight and both inguinal and epididymal fat mass were significantly reduced in KO compared to wild type control mice. On the other hand, we revealed that Nampt-mediated NAD synthesis was up-regulated during differentiation of 3T3-L1 preadipocytes and the inhibition of Nampt significantly suppressed the differentiation. Our metabolomic analysis and ChIP-qPCR assay showed NAD contributed to the differentiation through the metabolic reprogramming and the subsequent epigenetic alteration to activate the transcription of adipogenic genes. This result indicated Nampt-mediated NAD synthesis regulated differentiation of preadipocytes to mature adipocytes. Together, our data suggested that adipose tissue specific Nampt deletion resulted in the resistance against DIO and it could be partly attributed to the inhibited differentiation of preadipocytes.


K. Okabe: None. A. Nawaz: Research Support; Spouse/Partner; Astellas Pharma Inc., Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company. Research Support; Self; Japan Society for the Promotion of Science. Research Support; Spouse/Partner; Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Shionogi & Co., Ltd., Takeda Pharmaceutical Company Limited. S. Fujisaka: None. K. Yagi: None. T. Kado: None. I. Usui: None. T. Nakagawa: None. K. Tobe: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Japan Diabetes Society. Research Support; Self; Bristol-Myers Squibb Company.


Japan Society for the Promotion of Science

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