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

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  • Abudukadier Abulizi, Yale School of Medicine
  • ,
  • João Paulo Camporez, Yale School of Medicine
  • ,
  • Michael J. Jurczak, Yale School of Medicine
  • ,
  • Kasper F. Høyer
  • Dongyan Zhang, Yale School of Medicine
  • ,
  • Gary W. Cline, Yale School of Medicine
  • ,
  • Varman T. Samuel, Yale School of Medicine, VA Connecticut Healthcare System
  • ,
  • Gerald I. Shulman, Yale School of Medicine
  • ,
  • Daniel F. Vatner, Yale School of Medicine

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.

OriginalsprogEngelsk
TidsskriftF A S E B Journal
Vol/bind33
Nummer7
Sider (fra-til)8174-8185
Antal sider12
ISSN0892-6638
DOI
StatusUdgivet - jul. 2019

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