Inhibition of ADRP prevents diet-induced insulin resistance

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2008-09, Vol.295 (3), p.G621-G628
• Main Authors: Varela, Gladys M, Antwi, Daniel A, Dhir, Ravindra, Yin, Xiaoyan, Singhal, Neel S, Graham, Mark J, Crooke, Roseanne M, Ahima, Rexford S
• Format: Article
• Language: English
• Subjects: Adipose Tissue - enzymology; Animals; Blood Glucose - metabolism; Diet; Dietary Fats; Diglycerides - metabolism; Disease Models, Animal; Fatty Liver - enzymology; Fatty Liver - etiology; Fatty Liver - genetics; Fatty Liver - physiopathology; Fatty Liver - therapy; Genetic Therapy - methods; Homeostasis; Insulin; Insulin - metabolism; Insulin Resistance; Liver; Liver - enzymology; Liver and Biliary Tract; Liver diseases; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Muscle, Skeletal - enzymology; Oligonucleotides, Antisense - therapeutic use; Perilipin-2; Proteins; Rodents; Time Factors; Triglycerides - metabolism
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.90204.2008

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 PKCepsilon, consistent with its insulin-sensitizing action. These results demonstrate an important role for ADRP in the pathogenesis of diet-induced insulin resistance.