title: Molecular mechanism of moderate insulin resistance in adiponectin-knockout mice.
abstract: Adiponectin has been proposed to act as an antidiabetic adipokine, suppressing gluconeogenesis and stimulating fatty acid oxidation in the liver and skeletal muscle. Although adiponectin-knockout (adipo(-/-)) mice are known to exhibit insulin resistance, the degrees of insulin resistance and glucose intolerance are unexpectedly only moderate. In this study, the adipo(-/-) mice showed hepatic, but not muscle, insulin resistance. insulin-stimulated phosphorylation of IRS-1 and IRS-2 was impaired, the IRS-2 protein level was decreased, and insulin-stimulated phosphorylation of Akt was decreased in the liver of the adipo(-/-) mice. However, the triglyceride content in the liver was not increased in these mice, despite the decrease in the PPARalpha expression involved in lipid combustion, since the expressions of lipogenic genes such as SREBP-1 and SCD-1 were decreased in association with the increased leptin sensitivity. Consistent with this, the down-regulation SREBP-1 and SCD-1 observed in the adipo(-/-) mice was no longer observed, and the hepatic triglyceride content was significantly increased in the adiponectin leptin double-knockout (adipo(-/-)ob/ob) mice. On the other hand, the triglyceride content in the skeletal muscle was significantly decreased in the adipo(-/-) mice, probably due to up-regulated AMPK activity associated with the increased leptin sensitivity. In fact, these phenotypes in the skeletal muscle of these mice were no longer observed in the adipo(-/-)ob/ob mice. In conclusion, adipo(-/-) mice showed impaired insulin signaling in the liver to cause hepatic insulin resistance, however, no increase in the triglyceride content was observed in either the liver or the skeletal muscle, presumably on account of the increased leptin sensitivity.
authors.affiliation: Department of Diabetes and Metabolic Disease, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Yano
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Itoh
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kubota
authors.forename: Motoharu
authors.initials: M
authors.lastname: Awazawa
authors.forename: Masao
authors.initials: M
authors.lastname: Moroi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Sugi
authors.forename: Iseki
authors.initials: I
authors.lastname: Takamoto
authors.forename: Hitomi
authors.initials: H
authors.lastname: Ogata
authors.forename: Kumpei
authors.initials: K
authors.lastname: Tokuyama
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D052242:Adiponectin / Q000235:genetics; D000818:Animals; D015536:Down-Regulation; D015309:Glucose Clamp Technique; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D020738:Leptin / Q000235:genetics; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014280:Triglycerides / Q000032:analysis
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D007328:Insulin; D020738:Leptin; D014280:Triglycerides