title: Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity.
abstract: Adiponectin/Acrp30 is a hormone secreted by adipocytes, which acts as an antidiabetic and antiatherogenic adipokine. We reported previously that AdipoR1 and -R2 serve as receptors for adiponectin and mediate increased fatty acid oxidation and glucose uptake by adiponectin. In the present study, we examined the expression levels and roles of AdipoR1/R2 in several physiological and pathophysiological states such as fasting/refeeding, obesity, and insulin resistance. Here we show that the expression of AdipoR1/R2 in insulin target organs, such as skeletal muscle and liver, is significantly increased in fasted mice and decreased in refed mice. Insulin deficiency induced by streptozotocin increased and insulin replenishment reduced the expression of AdipoR1/R2 in vivo. Thus, the expression of AdipoR1/R2 appears to be inversely correlated with plasma insulin levels in vivo. Interestingly, the incubation of hepatocytes or myocytes with insulin reduced the expression of AdipoR1/R2 via the phosphoinositide 3-kinase/Foxo1-dependent pathway in vitro. Moreover, the expressions of AdipoR1/R2 in ob/ob mice were significantly decreased in skeletal muscle and adipose tissue, which was correlated with decreased adiponectin binding to membrane fractions of skeletal muscle and decreased AMP kinase activation by adiponectin. This adiponectin resistance in turn may play a role in worsening insulin resistance in ob/ob mice. In conclusion, the expression of AdipoR1/R2 appears to be inversely regulated by insulin in physiological and pathophysiological states such as fasting/refeeding, insulin deficiency, and hyper-insulinemia models via the insulin/phosphoinositide 3-kinase/Foxo1 pathway and is correlated with adiponectin sensitivity.
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tsuchida
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ito
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hada
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Maki
authors.forename: Sato
authors.initials: S
authors.lastname: Takekawa
authors.forename: Junji
authors.initials: J
authors.lastname: Kamon
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hara
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Jun
authors.initials: J
authors.lastname: Nakae
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D052242:Adiponectin; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D005227:Fatty Acids / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D018014:Gene Transfer Techniques; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D032342:Muscle Cells / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D054419:Receptors, Adiponectin; D011956:Receptors, Cell Surface / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013311:Streptozocin / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D005227:Fatty Acids; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D054419:Receptors, Adiponectin; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C475419:adiponectin receptor 1, mouse; D013311:Streptozocin; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose