In humans low levels of growth hormone (GH) and its mediator, insulin-like growth factor-1 (IGF-1), associate with hepatic lipid accumulation. In mice, congenital liver-specific ablation of the GH receptor (GHR) results in reductions in circulating IGF-1 and hepatic steatosis, associated with systemic insulin-resistance. Due to the intricate relationship between GH and IGF-1, the relative contribution of each hormone to the development of hepatic steatosis is unclear. Our goal was to dissect the mechanisms by which hepatic GH resistance leads to steatosis and overall insulin resistance, independent of IGF-1. We have generated a combined mouse model with liver-specific ablation of GHR in which we restored liver IGF-1 expression via hepatic IGF-1 transgene. We found that liver-GHR ablation leads to increases in lipid uptake, de novo lipogenesis, hyperinsulinemia and hyperglycemia accompanied with severe insulin resistance, and increased body adiposity and serum lipids. Restoration of IGF-1 improved overall insulin sensitivity, lipid profile in serum, reduced body adiposity, but was insufficient to protect against steatosis-induced hepatic inflammation or oxidative stress. We conclude that the impaired metabolism in states of GH resistance results from direct actions of GH on lipid uptake and de novo lipogenesis, while its actions on extrahepatic tissues are mediated by IGF-1.
- Received May 23, 2016.
- Accepted November 19, 2016.
- © 2016 by the American Diabetes Association.