Liver and adipose tissue are crucial for blood glucose and energy homeostasis, while impaired regulation of hepatic glucose production (HGP) and energy expenditure contribute to hyperglycemia and excessive fat storage in type 2 diabetes mellitus. Hepatokines are proteins secreted by hepatocytes, and several hepatokines have been shown to directly affect glucose and energy expenditure. In this study, we investigated the role of transforming growth factor beta 1 (TGF-β1) in hepatocytes in regulating glucose and energy homeostasis. We generated the liver-specific TGF-β1 knockout mice and found that the mice exhibited lower blood glucose, increased hepatic insulin sensitivity compared with wild type (WT) control mice. Using the mouse primary hepatocytes, we found that TGF-β1 deletion impaired HGP and TGF-β1 treatment promoted protein kinase A (PKA) signaling and stimulated the nuclear translocation of FoxO1. Under high fat diet (HFD) treatment, hepatic TGF-β1 deficiency protected mice from HFD-induced obesity and insulin resistance, decreased HGP and improved energy expenditure. Moreover, we used hepatic insulin receptor substrate-1, 2 (IRS1, 2) knockout (DKO) mice and deleted the TGF-β1 gene in the liver of DKO mice. We found that hepatic TGF-β1 ablation prevented hyperglycemia and hyperinsulinemia in DKO mice. Deletion of TGF-β1 or neutralization of TGF-β1 with antibody significantly decreased HGP of DKO hepatocytes. Additionally, hepatic TGF-β1 ablation enhanced thermogenesis and inguinal white adipose tissue (iWAT) browning in DKO mice. These findings underscore an important role of hepatic TGF-β1 in contribution to systemic glucose and energy homeostasis. Thus, hepatic TGF-β1 may serve as a therapeutic target for control of glucose and energy homeostasis in insulin resistance and type 2 diabetes mellitus.
Q. Pan: None. Y. Chen: None. D. Kim: None. Z. Shen: None. W. Yang: None. X. Li: None. Y. Sun: None. S. Guo: None.
American Diabetes Association (1-15-CD-09 to S.G.)