Inhibition of ADRP prevents diet-induced insulin resistance

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....

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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
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Summary: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.
ISSN:0193-1857
1522-1547
DOI:10.1152/ajpgi.90204.2008