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

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‐PKCe‐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., Hoyer, 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. FASEB J. 33, 8174–8185 (2019). www.fasebj.org