L‐Theanine Alleviates High‐Fat Diet‐Induced Obesity by Enhancing Hepatic Oxidative Phosphorylation and Remodeling Gut Microbiota to Augment Butyrate‐Producing

ABSTRACT Obesity represents a significant global health challenge, necessitating innovative therapeutic approaches. L‐theanine, a bioactive component in tea, possesses diverse biological activities. This study investigates the anti‐obesity mechanisms of L‐theanine, focusing on its effects on lipid metabolism, energy expenditure, and gut microbiota using both in vitro and in vivo models. In vitro, L‐theanine (2 mM) reduced hepatocyte lipid content by downregulating lipogenic genes. In vivo, 12‐week supplementation with L‐theanine (30 and 100 mg/kg/day) dose‐dependently decreased HFD‐induced body weight gain, adipose tissue mass, and serum triglycerides (TG) without altering food intake. Mechanistically, L‐theanine disturbed the transcription of some key genes closely related to thermogenesis, lipid oxidation, and glycolipid metabolism, with hepatic transcriptomics confirming the enrichment of oxidative phosphorylation and thermogenic pathways. Critically, L‐theanine also regulates gut microbiota, specifically increasing the abundance of Blautia and enhancing short‐chain fatty acid biosynthesis. Collectively, these findings indicate that L‐theanine shows promise as a multi‐target therapeutic agent for obesity, regulating lipid metabolism, enhancing energy expenditure, and maintaining gut microbiota homeostasis. However, its molecular targets, mechanisms, and human applicability still remain unclear.