Growth hormone control of hepatic lipid metabolism

Z Liu, J Cordoba-Chacon, RD Kineman… - Diabetes, 2016 - Am Diabetes Assoc
Z Liu, J Cordoba-Chacon, RD Kineman, BN Cronstein, R Muzumdar, Z Gong, H Werner
Diabetes, 2016Am Diabetes Assoc
In humans, low levels of growth hormone (GH) and its mediator, 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 …
In humans, low levels of growth hormone (GH) and its mediator, 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 the 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 and lipid profile in serum and 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, whereas its actions on extrahepatic tissues are mediated by IGF-1.
Am Diabetes Assoc