L-Theanine Activates the Browning of White Adipose Tissue Through the AMPK/a-Ketoglutarate/Prdm16 Axis and Ameliorates Diet-Induced Obesity in Mice

Abstract

L-Theanine is a nonprotein amino acid with much beneficial efficacy. We found that intraperitoneal treatment of the mice with L-theanine (100 mg/kg/day) enhanced adaptive thermogenesis and induced the browning of inguinal white adipose tissue (iWAT) with elevated expression of Prdm16, Ucp1, and other thermogenic genes. Meanwhile, administration of the mice with L-theanine increased energy expenditure. In vitro studies indicated that L-theanine induced the development of brown-like features in adipocytes. The shRNA-mediated depletion of Prdm16 blunted the role of L-theanine in promoting the brown-like phenotypes in adipocytes and in the iWAT of mice. L-theanine treatment enhanced AMPKa phosphorylation both in adipocytes and iWAT. Knock-down of AMPKa abolished L-theanine–induced upregulation of Prdm16 and adipocyte browning. L-Theanine increased the a-ketoglutarate (a-KG) level in adipocytes, which may increase the transcription of Prdm16 by inducing active DNA demethylation on its promoter. AMPK activation was required for L-theanine–induced increase of a-KG and DNA demethylation on the Prdm16 promoter. Moreover, intraperitoneal administration with L-theanine ameliorated obesity, improved glucose tolerance and insulin sensitivity, and reduced plasma triglyceride, total cholesterol, and free fatty acids in the high-fat diet–fed mice. Our results suggest a potential role of L-theanine in combating diet-induced obesity in mice, which may involve L-theanine–induced browning of WAT.