Growth hormone control of hepatic lipid metabolism

Zhongbo Liu, Jose Cordoba-Chacon, Rhonda D. Kineman, Bruce N. Cronstein, Radhika Muzumdar, Zhenwei Gong, Haim Werner, Shoshana Yakar

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3598-3609
Number of pages12
JournalDiabetes
Volume65
Issue number12
DOIs
StatePublished - Dec 1 2016

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Liu, Z., Cordoba-Chacon, J., Kineman, R. D., Cronstein, B. N., Muzumdar, R., Gong, Z., Werner, H., & Yakar, S. (2016). Growth hormone control of hepatic lipid metabolism. Diabetes, 65(12), 3598-3609. https://doi.org/10.2337/db16-0649