The role of cannabinoid 1 receptor in age-associated diseases - PROJECT SUMMARY Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease in the United States, affecting approximately 80 million adults. The prevalence of MASLD increases with age, and in older adults, it increases the risk of progression to more severe liver diseases. This highlights the urgent need for effective interventions to modify its course. Identifying previously unrecognized molecules contributing to MASLD could enhance our understanding of its underlying mechanisms and lead to more effective prevention strategies. Recent evidence suggests that the endocannabinoid system plays a crucial role in the development of obesity and type 2 diabetes, the primary metabolic drivers of MASLD, mainly through the activation of the cannabinoid 1 receptor (CB1R) in central and peripheral tissues, including the liver. Compounds that antagonize CB1R have shown promise as MASLD therapies by targeting both central and peripheral mechanisms. Specifically, focusing on hepatic CB1R is a promising approach for reducing lipogenesis and restoring glucose homeostasis without involving the central nervous system. While much progress has been made in targeting CB1R for MASLD and other liver diseases, the changes in the endocannabinoid system during the aging process have received relatively less attention. Thus, the objective of this proposal is to determine how hepatic CB1R contributes to age-dependent MASLD, which is exacerbated by aging hallmarks, particularly cellular senescence and gut dysbiosis. This objective is strongly supported by our preliminary data, demonstrating that: 1) hepatic CB1R deletion in diet-induced obese middle-aged mice reduces fat accumulation in both the whole body and liver, and downregulates lipogenesis-related genes; 2) liver-specific CB1R knockout mice are protected against MASLD- related metabolic abnormalities, including liver fat deposition, during aging; 3) hepatic CB1R deletion in aged mice significantly suppresses senescence-associated secretory phenotype (SASP) gene expressions; and 4) CB1R knockout in the liver reverses gut microbiome changes linked to aging. Based on these compelling findings, we hypothesize that hepatic CB1R is a key driver of age-associated MASLD and metabolic dysfunction. We proposed two specific aims: Aim 1: Identify the mechanisms of CB1R-driven hepatic steatosis by modulating age-dependent cellular senescence; and Aim 2: Determine the role of hepatic CB1R in age-associated MASLD through its interaction with the gut-liver axis and the microbiome. The proposed study will offer valuable training opportunities for undergraduate students. Furthermore, our findings will enhance our understanding of how peripheral CB1R antagonism can mitigate age-dependent metabolic changes associated with MASLD. Eventually, this work will lay the foundation for future clinical studies, aligned with our long-term goal of developing precise strategies to prevent MASLD throughout the lifespan.
