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. 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.
Varela
Gladys M
GM
Department of Medicine, Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, 415 Curie Blvd., 712A Clinical Research Bldg., Philadelphia, PA 19104, USA.
Antwi
Daniel A
DA
Dhir
Ravindra
R
Yin
Xiaoyan
X
Singhal
Neel S
NS
Graham
Mark J
MJ
Crooke
Roseanne M
RM
Ahima
Rexford S
RS
D000273:Adipose Tissue / Q000201:enzymology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004041:Dietary Fats; D004075:Diglycerides / Q000378:metabolism; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000201:enzymology; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D000070780:Perilipin-2; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D004041:Dietary Fats; D004075:Diglycerides; D007328:Insulin; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; D000070780:Perilipin-2; C000602983:Plin2 protein, mouse; D014280:Triglycerides