(P20-35-26) Protective Role of L-Theanine Against MASLD via Hepatic CB1R Signaling

Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent metabolic disorder characterized by hepatic lipid accumulation, insulin resistance, and systemic inflammation. Hepatic cannabinoid 1 receptor (CB1R) signaling plays a key role in regulating lipid metabolism and metabolic dysfunction in the liver. This study aimed to determine whether L-theanine, a bioactive compound found in tea, attenuates MASLD through modulation of hepatic CB1R signaling.

Methods: An 8-week dietary intervention was conducted using 4-week-old wild-type (WT) and liver-specific CB1R knockout (LCB1KO) male and female mice. Mice were fed either a normal chow diet or a high-fat, high-sugar diet with or without L-theanine supplementation administered via oral gavage (3 or 30 mg/kg body weight). Body weight and blood glucose levels were monitored throughout the study. At necropsy, metabolic organs, including liver and white adipose tissue, were collected for metabolic assessment.

Results: HFHSD feeding induced marked metabolic dysfunction in WT mice, including significant increases in body weight, liver weight, white adipose tissue mass, and both fed and fasting blood glucose levels compared with normal chow controls. L-theanine supplementation significantly attenuated these HFHSD-induced metabolic dysfunctions in WT mice, resulting in reduced body weight gain, decreased liver and adipose tissue mass, and improved glycemic control. In contrast, these metabolic improvements were markedly blunted in LCB1KO mice, indicating that the protective metabolic effects of L-theanine are largely mediated through hepatic CB1R signaling. Notably, the difference between WT and LCB1KO mice highlights a critical role for hepatic CB1R in mediating the metabolic benefits of L-theanine under obesogenic dietary conditions.

Conclusions: L-theanine supplementation ameliorates key metabolic features associated with MASLD, at least in part through CB1R-dependent mechanisms in the liver. These findings provide mechanistic insight into how targeted nutritional interventions may regulate hepatic metabolic signaling and supports the potential of L-theanine as a dietary strategy for the prevention or management of MASLD.

Funding Sources: This research is supported by USDA (2024-67018-42461).