Adipose TGR5 Deletion Promotes Hepatic Steatosis Through Decreasing Adiponectin Secretion in Mice.

Metabolic dysfunction–associated steatotic liver disease (MASLD) has emerged as a global epidemic, yet its underlying molecular mechanisms remain elusive, and therapeutic options are limited. The interorgan communication between liver and adipose tissue plays a crucial role in maintaining hepatic lipid homeostasis. This study investigates the role of G-protein–coupled bile acid receptor 1 (TGR5) in adipose tissue-liver communication and its impact on hepatic lipid metabolism during the progression of MASLD. We observed that TGR5 expression in white adipose tissue was significantly upregulated under both fasting and high-fat diet (HFD) conditions, whereas its levels in brown adipose tissue remained unchanged. Notably, mice with adipocyte-specific TGR5 deletion exhibited exacerbated fasting/HFD-induced hepatic steatosis and impaired hepatic fatty acid oxidation. Mechanistically, adipose tissue TGR5 deficiency reduced adiponectin secretion, which in turn suppressed hepatic fatty acid oxidation and aggravated hepatic lipid accumulation; conversely, restoration of circulating adiponectin rescued these metabolic abnormalities. Collectively, our findings highlight a critical role for adipose tissue TGR5 in promoting adiponectin secretion, thereby enhancing hepatic fatty acid oxidation and protecting against hepatic steatosis. ARTICLE HIGHLIGHTS: Systemic G-protein-coupled bile acid receptor 1 (TGR5) is involved in modulating hepatic triglyceride accumulation, but whether adipose-derived TGR5 regulates hepatic lipid metabolism remains undefined. We investigated whether fasting or a high-fat diet (HFD) altered TGR5 levels in adipose tissue and the effect of TGR5 ablation in adipose tissue on hepatic lipid metabolism. We found that TGR5 protein expression was upregulated in white adipose tissue upon fasting or HFD. Adipose-specific TGR5 deficiency decreased adiponectin secretion, which ultimately suppressed hepatic fatty acid oxidation and exacerbated intrahepatic lipid deposition. Given the limited therapeutic options for metabolic dysfunction-associated steatotic liver disease (MASLD), our findings highlight the therapeutic potential of targeting adipocyte TGR5 for MASLD intervention.