Ectopic lipid deposition mediates insulin resistance in adipose specific 11β-hydroxysteroid dehydrogenase type 1 transgenic mice

Metabolism. 2019 Apr:93:1-9. doi: 10.1016/j.metabol.2018.12.003. Epub 2018 Dec 19.

Abstract

Context: Excessive adipose glucocorticoid action is associated with insulin resistance, but the mechanisms linking adipose glucocorticoid action to insulin resistance are still debated. We hypothesized that insulin resistance from excess glucocorticoid action may be attributed in part to increased ectopic lipid deposition in liver.

Methods: We tested this hypothesis in the adipose specific 11β-hydroxysteroid dehydrogenase-1 (HSD11B1) transgenic mouse, an established model of adipose glucocorticoid excess. Tissue specific insulin action was assessed by hyperinsulinemic-euglycemic clamps, hepatic lipid content was measured, hepatic insulin signaling was assessed by immunoblotting. The role of hepatic lipid content was further probed by administration of the functionally liver-targeted mitochondrial uncoupler, Controlled Release Mitochondrial Protonophore (CRMP).

Findings: High fat diet fed HSD11B1 transgenic mice developed more severe hepatic insulin resistance than littermate controls (endogenous suppression of hepatic glucose production was reduced by 3.8-fold, P < 0.05); this was reflected by decreased insulin-stimulated hepatic insulin receptor kinase tyrosine phosphorylation and AKT serine phosphorylation. Hepatic insulin resistance was associated with a 53% increase (P < 0.05) in hepatic triglyceride content, a 73% increase in diacylglycerol content (P < 0.01), and a 66% increase in PKCε translocation (P < 0.05). Hepatic insulin resistance was prevented with administration of CRMP by reversal of hepatic steatosis and prevention of hepatic diacylglycerol accumulation and PKCε activation.

Conclusions: These findings are consistent with excess adipose glucocorticoid activity being a predisposing factor for the development of lipid (diacylglycerol-PKCε)-induced hepatic insulin resistance.

Keywords: Glucocorticoids; Insulin resistance; Nonalcoholic fatty liver disease; White adipose tissue.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / genetics*
  • Adipose Tissue / enzymology*
  • Animals
  • Diet, High-Fat
  • Glucocorticoids / metabolism
  • Insulin Resistance*
  • Lipid Metabolism*
  • Liver / metabolism*
  • Mice
  • Mice, Transgenic

Substances

  • Glucocorticoids
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1