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Diabetes. 2015 Sep;64(9):3093-103. doi: 10.2337/db15-0370. Epub 2015 May 26.

Growth Hormone Inhibits Hepatic De Novo Lipogenesis in Adult Mice.

Author information

1
Research and Development Division, Jesse Brown VA Medical Center, Chicago, IL Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL.
2
Edison Biotechnology Institute, Ohio University, Athens, OH Department of Specialty Medicine, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH.
3
Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD.
4
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL Endocrinology Section Medical Service, Birmingham VA Medical Center, Birmingham, AL.
5
Department of Physiological Sciences, University of Barcelona, L'Hospitalet, Barcelona, Spain.
6
Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH.
7
Edison Biotechnology Institute, Ohio University, Athens, OH Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH.
8
Research and Development Division, Jesse Brown VA Medical Center, Chicago, IL Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL kineman@uic.edu.

Abstract

Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have low growth hormone (GH) production and/or hepatic GH resistance. GH replacement can resolve the fatty liver condition in diet-induced obese rodents and in GH-deficient patients. However, it remains to be determined whether this inhibitory action of GH is due to direct regulation of hepatic lipid metabolism. Therefore, an adult-onset, hepatocyte-specific, GH receptor (GHR) knockdown (aLivGHRkd) mouse was developed to model hepatic GH resistance in humans that may occur after sexual maturation. Just 7 days after aLivGHRkd, hepatic de novo lipogenesis (DNL) was increased in male and female chow-fed mice, compared with GHR-intact littermate controls. However, hepatosteatosis developed only in male and ovariectomized female aLivGHRkd mice. The increase in DNL observed in aLivGHRkd mice was not associated with hyperactivation of the pathway by which insulin is classically considered to regulate DNL. However, glucokinase mRNA and protein levels as well as fructose-2,6-bisphosphate levels were increased in aLivGHRkd mice, suggesting that enhanced glycolysis drives DNL in the GH-resistant liver. These results demonstrate that hepatic GH actions normally serve to inhibit DNL, where loss of this inhibitory signal may explain, in part, the inappropriate increase in hepatic DNL observed in NAFLD patients.

PMID:
26015548
PMCID:
PMC4542445
DOI:
10.2337/db15-0370
[Indexed for MEDLINE]
Free PMC Article

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