Liver-specific deletion of the growth hormone receptor reveals essential role of growth hormone signaling in hepatic lipid metabolism

J Biol Chem. 2009 Jul 24;284(30):19937-44. doi: 10.1074/jbc.M109.014308. Epub 2009 May 21.

Abstract

Growth hormone (GH) plays a pivotal role in growth and metabolism, with growth promotion mostly attributed to generation of insulin-like growth factor I (IGF-I) in liver or at local sites of GH action, whereas the metabolic effects of GH are considered to be intrinsic to GH itself. To distinguish the effects of GH from those of IGF-I, we developed a Cre-lox-mediated model of tissue-specific deletion of the growth hormone receptor (GHR). Near total deletion of the GHR in liver (GHRLD) had no effect on total body or bone linear growth despite a >90% suppression of circulating IGF-I; however, total bone density was significantly reduced. Circulating GH was increased 4-fold, and GHRLD displayed insulin resistance, glucose intolerance, and increased circulating free fatty acids. Livers displayed marked steatosis, the result of increased triglyceride synthesis and decreased efflux; reconstitution of hepatic GHR signaling via adenoviral expression of GHR restored triglyceride output to normal, whereas IGF-I infusion did not correct steatosis despite restoration of circulating GH to normal. Thus, with near total absence of circulating IGF-I, GH action at the growth plate, directly and via locally generated IGF-I, can regulate bone growth, but at the expense of diabetogenic, lipolytic, and hepatosteatotic consequences. Our results indicate that IGF-I is essential for bone mineral density, whereas hepatic GH signaling is essential to regulate intrahepatic lipid metabolism. We propose that circulating IGF-I serves to amplify the growth-promoting effects of GH, while simultaneously dampening the catabolic effects of GH.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Body Weight
  • Bone Development
  • Carbohydrate Metabolism
  • Fatty Liver / genetics
  • Fatty Liver / metabolism
  • Gene Deletion
  • Gene Expression
  • Growth Hormone / metabolism*
  • Insulin Resistance
  • Insulin-Like Growth Factor I / metabolism*
  • Lipid Metabolism*
  • Liver / metabolism*
  • Liver / pathology
  • Mice
  • Receptors, Somatotropin / genetics*
  • Receptors, Somatotropin / metabolism*

Substances

  • Receptors, Somatotropin
  • Insulin-Like Growth Factor I
  • Growth Hormone