Growth Hormone Control of Hepatic Lipid Metabolism.
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.
Department of Basic Science & Craniofacial Biology, David B. Kriser Dental Center, NYU College of Dentistry, New York, NY.
Zhongbo
Z
Liu
Research and Development, Jesse Brown VA Medical Center, Chicago, IL.|Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL.
Jose
J
Cordoba-Chacon
Research and Development, Jesse Brown VA Medical Center, Chicago, IL.|Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL.
Rhonda D
RD
Kineman
Department of Medicine, NYU School of Medicine, New York, NY.
Bruce N
BN
Cronstein
Division of Pediatric Endocrinology, Diabetes and Metabolism Consultation, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Radhika
R
Muzumdar
Division of Pediatric Endocrinology, Diabetes and Metabolism Consultation, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Zhenwei
Z
Gong
Department of Human Molecular Genetics and Biochemistry, The Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel.
Haim
H
Werner
Department of Basic Science & Craniofacial Biology, David B. Kriser Dental Center, NYU College of Dentistry, New York, NY sy1007@nyu.edu.
Shoshana
S
Yakar
D000818:Animals; D015153:Blotting, Western; D005227:Fatty Acids / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism*; D006946:Hyperinsulinism / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D015227:Lipid Peroxidation / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism
D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D011986:Receptors, Somatotropin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D006003:Glycogen
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