Role of resistin in diet-induced hepatic insulin resistance.
Resistin is an adipose-derived hormone postulated to link adiposity to insulin resistance. To determine whether resistin plays a causative role in the development of diet-induced insulin resistance, we lowered circulating resistin levels in mice by use of a specific antisense oligodeoxynucleotide (ASO) directed against resistin mRNA and assessed in vivo insulin action by the insulin-clamp technique. After 3 weeks on a high-fat (HF) diet, mice displayed severe insulin resistance associated with an approximately 80% increase in plasma resistin levels. In particular, the rate of endogenous glucose production (GP) increased more than twofold compared with that in mice fed a standard chow. Treatment with the resistin ASO for 1 week normalized the plasma resistin levels and completely reversed the hepatic insulin resistance. Importantly, in this group of mice, the acute infusion of purified recombinant mouse resistin, designed to acutely elevate the levels of circulating resistin up to those observed in the HF-fed mice, was sufficient to reconstitute hepatic insulin resistance. These results provide strong support for a physiological role of resistin in the development of hepatic insulin resistance in this model.
Muse
Evan D
ED
Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, New York 10461, USA.
Obici
Silvana
S
Bhanot
Sanjay
S
Monia
Brett P
BP
McKay
Robert A
RA
Rajala
Michael W
MW
Scherer
Philipp E
PE
Rossetti
Luciano
L
D052242:Adiponectin; D000818:Animals; D002478:Cells, Cultured; D004032:Diet; D004041:Dietary Fats / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006729:Hormones, Ectopic / Q000097:blood* / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000097:blood; D008099:Liver / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D052243:Resistin
D052242:Adiponectin; D004041:Dietary Fats; D006729:Hormones, Ectopic; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D016376:Oligonucleotides, Antisense; D011506:Proteins; D011518:Proto-Oncogene Proteins; C499624:RETN protein, human; D011994:Recombinant Proteins; D052243:Resistin; C499623:Retn protein, mouse; C499622:Retn protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D005947:Glucose