title: Hyperadiponectinemia protects against premature death in metabolic syndrome model mice by inhibiting AKT signaling and chronic inflammation.
abstract: We previously reported that transgenic (Tg) expression of adiponectin significantly prolonged the lifespan of normal mice. The aim of this study was to elucidate the mechanism involved in the longevity effects of adiponectin using KK/Ta mice, a murine model of metabolic syndrome. We established a Tg line of KK/Ta (Tg-KK/Ta) mice expressing human adiponectin in the liver, and assessed their lifespan. The cause of death was determined by macroscopic and microscopic examinations immediately after death. The expressions of SIRT1, C-reactive protein (CRP), inflammatory cytokines, AMPK, and AKT were measured by quantitative real-time PCR, ELISAs, and/or western blotting. KK/Ta mice had lower serum adiponectin levels and shorter lifespan (57.6±13.9 vs 106.5±18.3 weeks, P<0.0001) than C57BL/6N mice. Tg adiponectin expression significantly extended the lifespan of KK/Ta mice (73.6±16.6 weeks, P<0.001) without affecting body weight, daily food consumption, or plasma glucose levels. Neoplasms were observed in only three of 22 KK/Ta mice that died spontaneously because of tumors. Atherosclerotic lesions were not detected in any mice. SIRT1 levels were not significantly different between KK/Ta and Tg-KK/Ta mice. Gene expressions of Crp, Tnfα, Il6, and Nfκb were increased in KK/Ta mice, but they were significantly attenuated in Tg-KK/Ta mice. Phosphorylated AMPK levels were increased and phosphorylated AKT levels were decreased in Tg-KK/Ta mice. The anti-inflammatory effects of adiponectin, achieved by inhibiting the AKT signaling pathway, may explain how adiponectin slows the accelerated aging process associated with the metabolic syndrome.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Otabe
authors.forename: N
authors.initials: N
authors.lastname: Wada
authors.forename: T
authors.initials: T
authors.lastname: Hashinaga
authors.forename: X
authors.initials: X
authors.lastname: Yuan
authors.forename: I
authors.initials: I
authors.lastname: Shimokawa
authors.forename: T
authors.initials: T
authors.lastname: Fukutani
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Ohki
authors.forename: S
authors.initials: S
authors.lastname: Kakino
authors.forename: Y
authors.initials: Y
authors.lastname: Kurita
authors.forename: H
authors.initials: H
authors.lastname: Nakayama
authors.forename: Y
authors.initials: Y
authors.lastname: Tajiri
authors.forename: K
authors.initials: K
authors.lastname: Yamada
mesh_terms: D052242:Adiponectin / Q000097:blood* / Q000235:genetics; D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061213:Mortality, Premature; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; D051057:Proto-Oncogene Proteins c-akt