Regulation of Hepatic Glucose Production by Transforming Growth Factor Beta 1 via Protein Kinase A

Hepatic glucose production (HGP) is crucial for blood glucose homeostasis, while an impaired regulation of HGP contributes to hyperglycemia in patients with type 2 diabetes mellitus. Hepatokines are proteins secreted by hepatocytes, and some of them can directly affect glucose metabolism. Here we examined the role of transforming growth factor beta 1 (TGF-β1) in regulating glucose homeostasis. We generated the liver-specific TGF-beta1 knockout mice and found that hepatic TGF-β1 deficient mice exhibited a lower blood glucose levels. Hepatic TGF-β1 deficiency increased insulin sensitivity and protected mice from diet-induced obesity and hyperglycemia. In vitro studies using mouse primary hepatocytes, TGF-β1 augmented glycogenolysis and gluconeogenesis, activated protein kinase A (PKA) signaling, promoted the stability of the O-class of the forkhead transcription factor 1 (Foxo1), and increased the level of key gluconeogenic genes, glucose-6-phosphatase (G6Pase) and phosphorenolpyruvate carboxykinase (PEPCK). These findings underscore an important role of hepatic TGF-β1 in contribution to blood glucose homeostasis, and hepatic TGF-β1 may serve as an important hepatokine and therapeutic target for glycemic control in insulin resistance and type 2 diabetes mellitus.