Diet-induced insulin resistance in mice lacking adiponectin/ACRP30.
Here we investigated the biological functions of adiponectin/ACRP30, a fat-derived hormone, by disrupting the gene that encodes it in mice. Adiponectin/ACRP30-knockout (KO) mice showed delayed clearance of free fatty acid in plasma, low levels of fatty-acid transport protein 1 (FATP-1) mRNA in muscle, high levels of tumor necrosis factor-alpha (TNF-alpha) mRNA in adipose tissue and high plasma TNF-alpha concentrations. The KO mice exhibited severe diet-induced insulin resistance with reduced insulin-receptor substrate 1 (IRS-1)-associated phosphatidylinositol 3 kinase (PI3-kinase) activity in muscle. Viral mediated adiponectin/ACRP30 expression in KO mice reversed the reduction of FATP-1 mRNA, the increase of adipose TNF-alpha mRNA and the diet-induced insulin resistance. In cultured myocytes, TNF-alpha decreased FATP-1 mRNA, IRS-1-associated PI3-kinase activity and glucose uptake, whereas adiponectin increased these parameters. Our results indicate that adiponectin/ACRP30 deficiency and high TNF-alpha levels in KO mice reduced muscle FATP-1 mRNA and IRS-1-mediated insulin signaling, resulting in severe diet-induced insulin resistance.
Maeda
Norikazu
N
Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan.
Shimomura
Iichiro
I
Kishida
Ken
K
Nishizawa
Hitoshi
H
Matsuda
Morihiro
M
Nagaretani
Hiroyuki
H
Furuyama
Naoki
N
Kondo
Hidehiko
H
Takahashi
Masahiko
M
Arita
Yukio
Y
Komuro
Ryutaro
R
Ouchi
Noriyuki
N
Kihara
Shinji
S
Tochino
Yoshihiro
Y
Okutomi
Keiichi
K
Horie
Masato
M
Takeda
Satoshi
S
Aoyama
Toshifumi
T
Funahashi
Tohru
T
Matsuzawa
Yuji
Y
D052242:Adiponectin; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004032:Diet; D050556:Fatty Acid-Binding Proteins; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D029941:Fish Proteins; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D052242:Adiponectin; D002352:Carrier Proteins; C425124:FABP-1 protein, Lateolabrax japonicus; D050556:Fatty Acid-Binding Proteins; D005230:Fatty Acids, Nonesterified; D029941:Fish Proteins; D055504:Insulin Receptor Substrate Proteins; D036341:Intercellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D011506:Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases