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FASEB J. 2019 Jul;33(7):8174-8185. doi: 10.1096/fj.201802706R. Epub 2019 Mar 28.

Adipose glucocorticoid action influences whole-body metabolism via modulation of hepatic insulin action.

Author information

1
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
2
Department of Clinical Medicine, Magnetic Resonance Research Centre, Aarhus University, Aarhus, Denmark.
3
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
4
Veterans Affairs Medical Center, West Haven, Connecticut, USA.
5
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA.

Abstract

The connection between adipose glucocorticoid action and whole-body metabolism is incompletely understood. Thus, we generated adipose tissue-specific glucocorticoid receptor-knockout (Ad-GcR-/-) mice to explore potential mechanisms. Ad-GcR-/- mice had a lower concentration of fasting plasma nonesterified fatty acids and less hepatic steatosis. This was associated with increased protein kinase B phosphorylation and increased hepatic glycogen synthesis after an oral glucose challenge. High-fat diet (HFD)-fed Ad-GcR-/- mice were protected against the development of hepatic steatosis and diacylglycerol-PKCε-induced impairments in hepatic insulin signaling. Under hyperinsulinemic-euglycemic conditions, hepatic insulin response was ∼10-fold higher in HFD-fed Ad-GcR-/- mice. Insulin-mediated suppression of adipose lipolysis was improved by 40% in Ad-GcR-/- mice. Adipose triglyceride lipase expression was decreased and insulin-mediated perilipin dephosphorylation was increased in Ad-GcR-/- mice. In metabolic cages, food intake decreased by 3 kcal/kg per hour in Ad-GcR-/- mice. Therefore, physiologic adipose glucocorticoid action appears to drive hepatic lipid accumulation during stressors such as fasting. The resultant hepatic insulin resistance prevents hepatic glycogen synthesis, preserving glucose for glucose-dependent organs. Absence of adipose glucocorticoid action attenuates HFD-induced hepatic insulin resistance; potential explanations for reduction in hepatic steatosis include reductions in adipose lipolysis and food intake.-Abulizi, A., Camporez, J.-P., Jurczak, M. J., Høyer, K. F., Zhang, D., Cline, G. W., Samuel, V. T., Shulman, G. I., Vatner, D. F. Adipose glucocorticoid action influences whole-body metabolism via modulation of hepatic insulin action.

KEYWORDS:

glycogen synthesis; hepatic steatosis; insulin resistance; white adipose tissue

PMID:
30922125
PMCID:
PMC6593882
[Available on 2020-04-28]
DOI:
10.1096/fj.201802706R

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