1614-P: Metabolomic Profiling Reveals Thiamine-Mediated Regulation of Triglyceride Synthesis and Lipid Turnover in Brown Fat

Abstract

Brown adipose tissue (BAT) functions as a metabolic sink to dispose glucose as well as fatty acids (FAs) and exerts profound effects on energy and glucose homeostasis. Intermittent fasting (IF) has become an attractive option for combating obesity and treating diabetes, yet how IF regimen impacts BAT metabolism and thermogenic capacity remains poorly understood. Using metabolomics and lipidomic assays, we show that alternate day fasting (ADF) elicited robust activation of upper glycolysis and increased production of glycerol-3-phosphate (G3P) and lactate accompanied with stimulation of glycolytic shunts, pentose phosphate pathway (PPP) and glycogenesis, in BAT but not in gonadal white adipose tissue (gWAT) in feeding state. As a result, feast BAT exhibited a notable increase in triglyceride (TG) synthesis, tissue volume, and thermogenic capacity compared to ad libitum group. Mechanistically, repeated fasting and refeeding suppressed the expression of thiamine transporter ThTr2 and decreased the levels of free thiamine, thiamine pyrophosphate (TPP) and thiamine monophosphate (TMP), in part through periodic activation of mTORC1. Genetic inhibition of mTORC1 in BAT restored expression of ThTr2 and diminished ADF-preserved lipid storage in vivo, and inactivating thiamine metabolism with specific inhibitors induced G3P production and TG synthesis in vitro. Taken together, our study reveals a new mechanism involving thiamine that reprograms BAT carbohydrate metabolism to preserve lipids and improves metabolic health. Disclosure C.Wang: None. X.Zhang: None. M.Liu: None.