Insulin decreases myocardial adiponectin receptor 1 expression via PI3K/Akt and FoxO1 pathway.
OBJECTIVE
Adiponectin is considered an important adipokine protecting against diabetes, atherosclerosis, and cardiovascular disease. Because adiponectin receptors (AdipoRs) are critical components in the adiponectin signalling cascade, we investigated the effect of insulin on the expression of myocardial AdipoRs and explored the possible molecular mechanism.


RESULTS
The hyperinsulinaemia rat model was induced by infusion of insulin (1 U/day) for 28 days: serum and myocardial adiponectin levels were increased, and skeletal muscle and myocardial AdipoR1 expression and AMP-activated protein kinase (AMPK) phosphorylation were decreased. In primary cultured neonatal rat ventricular myocytes (NRVMs), insulin decreased AdipoR1 but not AdipoR2 expression and AMPK phosphorylation; high glucose had no affect on AdipoRs expression. Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation was increased in insulin-treated hearts and in NRVMs. P13K inhibitor LY294002 and Akt1/2 kinase inhibitor but not the ERK1/2 kinase (MEK) inhibitors PD98059 and U0126 blocked the insulin-induced reduction in AdipoR1 expression and AMPK phosphorylation. Insulin induced forkhead/winged helix box gene group O-1 (FoxO1) phosphorylation and translocation from the nucleus to the cytosol, and this was blocked by LY294002. FoxO1 small interfering RNA reduced AdipoR1 expression and AMPK phosphorylation. In electrophoretic mobility shift assay and chromatin immunoprecipitation, FoxO1 bound to the putative site from -167 to -157 bp of the AdipoR1 promoter both in vitro and in living cells; insulin suppressed this binding, which was blocked by LY294002.


CONCLUSIONS
Insulin inhibits myocardial AdipoR1 expression via PI3K/Akt and FoxO1 pathways, and FoxO1 mediates AdipoR1 transcription by binding to its promoter directly.
Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
Xiao-Bing
XB
Cui
Cheng
C
Wang
Li
L
Li
Dong
D
Fan
Yun
Y
Zhou
Dan
D
Wu
Qing-Hua
QH
Cui
Feng-Ying
FY
Fu
Li-Ling
LL
Wu
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D054419:Receptors, Adiponectin / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071161:Forkhead Box Protein O1
D055372:AMP-Activated Protein Kinases; D051858:Forkhead Transcription Factors; D007328:Insulin; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054419:Receptors, Adiponectin; C504339:adiponectin receptor 1, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1