Inhibition of ADRP prevents diet-induced insulin resistance

Gladys M. Varela, Daniel A. Antwi, Ravindra Dhir, Xiaoyan Yin, Neel S. Singhal, Mark J. Graham, Roseanne M. Crooke, Rexford S. Ahima

Research output: Contribution to journalArticlepeer-review

Abstract

Diets with high fat content induce steatosis, insulin resistance, and type 2 diabetes. The lipid droplet protein adipose differentiation-related protein (ADRP) mediates hepatic steatosis, but whether this affects insulin action in the liver or peripheral organs in diet-induced obesity is uncertain. We fed C57BL/6J mice a high-fat diet and simultaneously treated them with an antisense oligonucleotide (ASO) against ADRP for 4 wk. Glucose homeostasis was assessed with clamp and tracer techniques. ADRP ASO decreased the levels of triglycerides and diacylglycerol in the liver, but fatty acids, long-chain fatty acyl CoAs, ceramides, and cholesterol were unchanged. Insulin action in the liver was enhanced after ADRP ASO treatment, whereas muscle and adipose tissue were not affected. ADRP ASO increased the phosphorylation of insulin receptor substrate (IRS)1, IRS2, and Akt, and decreased gluconeogenic enzymes and PKCε, consistent with its insulin-sensitizing action. These results demonstrate an important role for ADRP in the pathogenesis of diet-induced insulin resistance.

Original languageEnglish (US)
Pages (from-to)G621-G628
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume295
Issue number3
DOIs
StatePublished - Sep 2008
Externally publishedYes

Keywords

  • Adipose differentiation-related protein
  • Liver
  • Steatosis

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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