IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α- and obesity-induced insulin resistance

Science

Volumn 271, Issue 5249, 1996, Pages 665-668

  Hotamisligil, Gökhan S ^a,b   Peraldi, Pascal ^a   Budavari, Adriane ^a   Ellis, Ramsey ^a   White, Morris F ^a   Spiegelman, Bruce M ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

^b HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

INSULIN RECEPTOR KINASE; TUMOR NECROSIS FACTOR ALPHA;

ADIPOCYTE; ADIPOSE TISSUE; ANIMAL CELL; ANIMAL TISSUE; ARTICLE; BONE MARROW CELL; CELL CULTURE; CONTROLLED STUDY; DIABETES MELLITUS; ENZYME ACTIVITY; ENZYME INHIBITION; GENETIC TRANSFECTION; INSULIN RESISTANCE; MOUSE; MUSCLE; NONHUMAN; OBESITY; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; RAT; SIGNAL TRANSDUCTION;

ANIMALIA; MURINAE;

EID: 0030061922     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.271.5249.665     Document Type: Article

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27. 32P]orthophosphate (3 mCi/ml, 6000 Ci/mmol, New England Nuclear) was added and incubation was continued for 3 hours at 37°C Insulin stimulations were done by adding insulin (100 ng/ml) directly to the medium. Plates were washed with ice-cold PBS once and protein extracts were prepared as described, Immunoprecipitations were done from control and TNF-α-treated cells with polyclonal antibodies to IR and IRS-1 and a monoclonal antibody to phosphotyrosine in a 1:100 (v/v) dilution for 4 hours and analyzed by SDS-polyacrylamide gel electrophoresis (PAGE) and autoradiography.
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29. Specific pathogen-free, male Zucker obese (fa/fa) rats and their lean controls (+/?) were purchased from Charles River Laboratones. On arrival, rats were housed for at least 1 week before the experimental procedures were begun and fed standard rodent chow and water ad libitum After a 6-hour fast, rats were anesthetized with ketamine and xylasine (intramuscular), the abdominal cavity was opened, and fat (epididymal), muscle (hind limb), and liver tissues were removed and frozen immediately in liquid nitrogen. Frozen tissues were ground into a fine powder with a mortar and pestle and then homogenized with a Polytron homogenizer at 4°C in 6x the tissue volume of homogemzation buffer [1% Triton X-100, 150mM NaCl, 10 mM Hepes(pH 7.4), 250 mM sucrose, 10 mM EDTA, 10 mM EGTA, 10 mM benzamidine, 2 mM phenylmethylsulfonyl fluoride (PMSF), and aprotinin (100 μg/ml)]. All extracts were centrifuged at 12,000 rpm for 30 min at 4°C, and the supernatants were collected for further analysis All animal procedures were in accordance with institutional guidelines.
30. We thank C. Carpenter for phosphoamino acid analysis, M Myers Jr. and B. Cheatham for gifts of 320 cells and other reagents, and C. R Kahn for reviewing the manuscript. Supported by a grant from the National Institutes of Health (DK 42539 to B.M S.) and fellowships from the American Diabetes Association (G.S.H.) and from the Association pour la Recherché sur le Cancer and Juveniles Diabetes Foundation International (P.P.)