Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function

被引:1782
作者
Uysal, KT
Wiesbrock, SM
Marino, MW
Hotamisligil, GS
机构
[1] HARVARD UNIV,SCH PUBL HLTH,DIV BIOL SCI,BOSTON,MA 02115
[2] HARVARD UNIV,SCH PUBL HLTH,DEPT NUTR,BOSTON,MA 02115
[3] MEM SLOAN KETTERING CANC CTR,LUDWIG INST CANC RES,NEW YORK,NY 10021
关键词
D O I
10.1038/39335
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Obesity is highly associated with insulin resistance and is the biggest risk factor for non-insulin-dependent diabetes mellitus(1-3). The molecular basis of this common syndrome, however, is poorly understood. It has been suggested that tumour necrosis factor (TNF)-alpha is a candidate mediator of insulin resistance in obesity as it is overexpressed in the adipose tissues of rodents and humans(4-10) and it blocks the action of insulin in cultured cells and whole animals(10-14). To investigate the role of TNF-alpha in obesity and insulin resistance, we have generated obese mice with a targeted null mutation in the gene encoding TNF-alpha and those encoding the two receptors for TNF-alpha. The absence of TNF-alpha resulted in significantly improved insulin sensitivity in both diet-induced obesity and that resulting for the ob/ob model of obesity. The TNF alpha-deficient obese mice had lower levels of circulating free fatty acids, and were protected from the obesity-related reduction in the insulin receptor signalling in muscle and fat tissues, These results indicate that TNF-alpha is an important mediator of insulin resistance in obesity through its effects on several important sites of insulin action.
引用
收藏
页码:610 / 614
页数:5
相关论文
共 26 条
[11]   Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein [J].
Hotamisligil, GS ;
Johnson, RS ;
Distel, RJ ;
Ellis, R ;
Papaioannou, VE ;
Spiegelman, BM .
SCIENCE, 1996, 274 (5291) :1377-1379
[12]   IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance [J].
Hotamisligil, GS ;
Peraldi, P ;
Budavari, A ;
Ellis, R ;
White, MF ;
Spiegelman, BM .
SCIENCE, 1996, 271 (5249) :665-668
[13]   ADIPOSE EXPRESSION OF TUMOR-NECROSIS-FACTOR-ALPHA - DIRECT ROLE IN OBESITY-LINKED INSULIN RESISTANCE [J].
HOTAMISLIGIL, GS ;
SHARGILL, NS ;
SPIEGELMAN, BM .
SCIENCE, 1993, 259 (5091) :87-91
[14]   TUMOR-NECROSIS-FACTOR-ALPHA INHIBITS SIGNALING FROM THE INSULIN-RECEPTOR [J].
HOTAMISLIGIL, GS ;
MURRAY, DL ;
CHOY, LN ;
SPIEGELMAN, BM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (11) :4854-4858
[15]   INCREASED ADIPOSE-TISSUE EXPRESSION OF TUMOR-NECROSIS-FACTOR-ALPHA IN HUMAN OBESITY AND INSULIN-RESISTANCE [J].
HOTAMISLIGIL, GS ;
ARNER, P ;
CARO, JF ;
ATKINSON, RL ;
SPIEGELMAN, BM .
JOURNAL OF CLINICAL INVESTIGATION, 1995, 95 (05) :2409-2415
[16]   REDUCED TYROSINE KINASE-ACTIVITY OF THE INSULIN-RECEPTOR IN OBESITY-DIABETES - CENTRAL ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA [J].
HOTAMISLIGIL, GS ;
BUDAVARI, A ;
MURRAY, D ;
SPIEGELMAN, BM .
JOURNAL OF CLINICAL INVESTIGATION, 1994, 94 (04) :1543-1549
[17]   Differential regulation of the p80 tumor necrosis factor receptor in human obesity and insulin resistance [J].
Hotamisligil, GS ;
Arner, P ;
Atkinson, RL ;
Spiegelman, BM .
DIABETES, 1997, 46 (03) :451-455
[18]   TUMOR-NECROSIS-FACTOR-ALPHA INDUCED PHOSPHORYLATION OF INSULIN-RECEPTOR SUBSTRATE-1 (IRS-1) - POSSIBLE MECHANISM FOR SUPPRESSION OF INSULIN-STIMULATED TYROSINE PHOSPHORYLATION OF IRS-1 [J].
KANETY, H ;
FEINSTEIN, R ;
PAPA, MZ ;
HEMI, R ;
KARASIK, A .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (40) :23780-23784
[19]   THE EXPRESSION OF TUMOR-NECROSIS-FACTOR IN HUMAN ADIPOSE-TISSUE - REGULATION BY OBESITY, WEIGHT-LOSS, AND RELATIONSHIP TO LIPOPROTEIN-LIPASE [J].
KERN, PA ;
SAGHIZADEH, M ;
ONG, JM ;
BOSCH, RJ ;
DEEM, R ;
SIMSOLO, RB .
JOURNAL OF CLINICAL INVESTIGATION, 1995, 95 (05) :2111-2119
[20]   Tumor necrosis factor-alpha- and hyperglycemia-induced insulin resistance - Evidence for different mechanisms and different effects on insulin signaling [J].
Kroder, G ;
Bossenmaier, B ;
Kellerer, M ;
Capp, E ;
Stoyanov, B ;
Muhlhofer, A ;
Berti, L ;
Horikoshi, H ;
Ullrich, A ;
Haring, H .
JOURNAL OF CLINICAL INVESTIGATION, 1996, 97 (06) :1471-1477