第124回日本医学会シンポジウム

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1 III γ γ γ α γ Molecular Mechanism of Insulin Resistance by Adipocytes TAKASHI KADOWAKI Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo Key words γ

2 TNFα FFA 1,2 TNFα FFA 1,2 FFA FA-CoA IRS-1 IRS-2 PPARγ α 111

3 γ α α γ α

4 PPARγ 4 DNA 4,5PPARγ TNFα Acrp 30 AdipoQ GBP 28 5,6 FFA Ad globular gad FFA γ α α 113

5 2 6 2 KKAy 6 6,7 in vitro PPARα 8PPARα CoA ACO β UCP 2 AMP β α

6 PPARγ PPARγ 5 6,10 10 FACS fluorescence-activated cell sorter γ γ γ γ γ γ α PPARγ 115

7 α α cdna small interfering si RNA Globular cdna

8 α 7 AdipoR 1 AdipoR AdipoR 2 AdipoR 1 AdipoR 2 AdipoR 1 R2 7 G GPCR N C topology GPCR AdipoR 1 R2 globular AMPK p38mapk PPARα AdipoR AMPK p38mapk AdipoR AMPK p38mapk sirna AdipoR 1 R2 globular PPARα 8 9 AdipoR 1 R2 globular AMPK p38mapk PPARα AdipoR 1 R

9 1 Okuno A, Tamemoto H, Tobe K, et al. :Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. JClinInvest1998 ; 101 : Yamauchi T, Kamon J, Waki H, et al. : The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma PPAR gamma deficiency and PPAR gamma agonist improve insulin resistance. JBiolChem2001 ; 276 : Kadowaki T : Insights into insulin resistance and type 2 diabetes from knockout mouse models. JClinInvest 2000 ; 106 : Kubota N, Terauchi Y, Miki H, et al. : PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 1999 ; 4 : Yamauchi T, Waki H, Kamon J, et al. : Inhibition of RXR and PPAR gamma ameliorates diet-induced obesity and type 2 diabetes. JClinInvest2001 ; 108 : Yamauchi T, Kamon J, Waki H, et al. : The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Medicine 2001 ; 7 : Hara K, Boutin P, Mori Y, et al. : Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes 2002 ; 51 : Yamauchi T, Kamon J, Waki H, et al. : Globular adiponectin protected ob ob mice from diabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem 2003 ; 278 : Yamauchi T, Kamon J, Minokoshi Y, et al. :Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nature Medicine 2002 ; 8 : Yamauchi T, Kamon J, Ito Y, et al. : Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003 ; 423 : T3L1 3T3L1 TNF-α cis-acting element in vitro TNF-α NF-κB TNF-α TNF-α TNF-α

10 β β β Adipo R 1 Adipo R 2 β β SNP SNP 2 SNP Reitman 119

11 Reitman Reitman Reitman Reitman Diabetes Reitman G C N C N N reviewer C N G C N

12 7 Adipo R 1 121

SMXA-5

SMXA-5 2 Key words 2 Type 2 diabetes Insulin resistance Impairement of insulin secretion Spontaneously diabetic model animal high-fat diet diabetogenic gene 1 2 2 2 2 2 1 2 2 SMXA-5 3 SM.A-T2dm2sa SMXA-5 SM/J

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