| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLES |
-Mediated Insulin Resistance in Genetic Obesity1
Division of Biological Sciences and Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Gökhan S. Hotamisligil, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115. E-mail: ghotamis{at}hsph.harvard.edu
Although obesity has become the most common metabolic disorder in the
developed world and is highly associated with insulin resistance and
noninsulin-dependent diabetes mellitus, the molecular mechanisms
underlying these disorders are not clearly understood. Tumor necrosis
factor-
(TNF-) is overexpressed in obesity and is a candidate
mediator of obesity-induced insulin resistance. Complete lack of
TNF- function through targeted mutations in TNF- gene or both of
its receptors results in significant improvement of insulin sensitivity
in dietary, chemical, or genetic models of rodent obesity. In this
study, we have analyzed the in vivo role of TNF
signaling from p55 [TNF receptor (TNFR) 1] and p75 (TNFR 2)
TNFR in the development of insulin resistance by generating
genetically obese mice (ob/ob) lacking p55 or p75 TNFRs.
In the ob/ob mice, the absence of p55 caused a
significant improvement in insulin sensitivity. p75 deficiency alone
did not affect insulin sensitivity but might potentiate the effects of
p55 deficiency in animals lacking both TNFRs. These results indicate
that TNF- is a component of insulin resistance in the
ob/ob model of murine obesity and p55 TNFR is the
predominant receptor mediating its actions.
This article has been cited by other articles:
 |
|
 |
|
  I. Zschiedrich, U. Hardeland, A. Krones-Herzig, M. Berriel Diaz, A. Vegiopoulos, J. Muggenburg, D. Sombroek, T. G. Hofmann, R. Zawatzky, X. Yu, et al. Coactivator function of RIP140 for NF{kappa}B/RelA-dependent cytokine gene expression Blood, July 15, 2008; 112(2): 264 - 276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Liang, B. Yin, H. Zhang, S. Zhang, Q. Zeng, J. Wang, X. Jiang, L. Yuan, C.-Y. Wang, and Z. Li Blockade of Tumor Necrosis Factor (TNF) Receptor Type 1-Mediated TNF-{alpha} Signaling Protected Wistar Rats from Diet-Induced Obesity and Insulin Resistance Endocrinology, June 1, 2008; 149(6): 2943 - 2951. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Y. Donath, J. Storling, L. A. Berchtold, N. Billestrup, and T. Mandrup-Poulsen Cytokines and {beta}-Cell Biology: from Concept to Clinical Translation Endocr. Rev., May 1, 2008; 29(3): 334 - 350. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Serino, R. Menghini, L. Fiorentino, R. Amoruso, A. Mauriello, D. Lauro, P. Sbraccia, M. L. Hribal, R. Lauro, and M. Federici Mice Heterozygous for Tumor Necrosis Factor-{alpha} Converting Enzyme Are Protected From Obesity-Induced Insulin Resistance and Diabetes Diabetes, October 1, 2007; 56(10): 2541 - 2546. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. De Taeye, T. Novitskaya, O. P. McGuinness, L. Gleaves, M. Medda, J. W. Covington, and D. E. Vaughan Macrophage TNF-{alpha} contributes to insulin resistance and hepatic steatosis in diet-induced obesity Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E713 - E725. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Liao, M. T. A. Nguyen, T. Yoshizaki, S. Favelyukis, D. Patsouris, T. Imamura, I. M. Verma, and J. M. Olefsky Suppression of PPAR-{gamma} attenuates insulin-stimulated glucose uptake by affecting both GLUT1 and GLUT4 in 3T3-L1 adipocytes Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E219 - E227. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Popa, M. G. Netea, P. L. C. M. van Riel, J. W. M. van der Meer, and A. F. H. Stalenhoef The role of TNF-{alpha} in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk J. Lipid Res., April 1, 2007; 48(4): 751 - 762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Moloney, S. Toomey, E. Noone, A. Nugent, B. Allan, C. E. Loscher, and H. M. Roche Antidiabetic Effects of cis-9, trans-11-Conjugated Linoleic Acid May Be Mediated via Anti-Inflammatory Effects in White Adipose Tissue Diabetes, March 1, 2007; 56(3): 574 - 582. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Nieto-Vazquez, S. Fernandez-Veledo, C. de Alvaro, C. M. Rondinone, A. M. Valverde, and M. Lorenzo Protein-Tyrosine Phosphatase 1B-Deficient Myocytes Show Increased Insulin Sensitivity and Protection Against Tumor Necrosis Factor-{alpha}-Induced Insulin Resistance Diabetes, February 1, 2007; 56(2): 404 - 413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Trujillo and P. E. Scherer Adipose Tissue-Derived Factors: Impact on Health and Disease Endocr. Rev., December 1, 2006; 27(7): 762 - 778. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Imoto, D. Kukidome, T. Nishikawa, T. Matsuhisa, K. Sonoda, K. Fujisawa, M. Yano, H. Motoshima, T. Taguchi, K. Tsuruzoe, et al. Impact of mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on insulin signaling. Diabetes, May 1, 2006; 55(5): 1197 - 1204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Neels, M. Pandey, G. S. Hotamisligil, and F. Samad Autoamplification of Tumor Necrosis Factor-{alpha}: A Potential Mechanism for the Maintenance of Elevated Tumor Necrosis Factor-{alpha} in Male but Not Female Obese Mice Am. J. Pathol., February 1, 2006; 168(2): 435 - 444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Puga, B. Lainez, J. M. Fernandez-Real, M. Buxade, M. Broch, J. Vendrell, and E. Espel A Polymorphism in the 3' Untranslated Region of the Gene for Tumor Necrosis Factor Receptor 2 Modulates Reporter Gene Expression Endocrinology, May 1, 2005; 146(5): 2210 - 2220. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Summers and D. H. Nelson A Role for Sphingolipids in Producing the Common Features of Type 2 Diabetes, Metabolic Syndrome X, and Cushing's Syndrome Diabetes, March 1, 2005; 54(3): 591 - 602. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Boord, K. Maeda, L. Makowski, V. R. Babaev, S. Fazio, M. F. Linton, and G. S. Hotamisligil Combined Adipocyte-Macrophage Fatty Acid-Binding Protein Deficiency Improves Metabolism, Atherosclerosis, and Survival in Apolipoprotein E-Deficient Mice Circulation, September 14, 2004; 110(11): 1492 - 1498. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. de Alvaro, T. Teruel, R. Hernandez, and M. Lorenzo Tumor Necrosis Factor {alpha} Produces Insulin Resistance in Skeletal Muscle by Activation of Inhibitor {kappa}B Kinase in a p38 MAPK-dependent Manner J. Biol. Chem., April 23, 2004; 279(17): 17070 - 17078. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Radaelli, A. Varastehpour, P. Catalano, and S. Hauguel-de Mouzon Gestational Diabetes Induces Placental Genes for Chronic Stress and Inflammatory Pathways Diabetes, December 1, 2003; 52(12): 2951 - 2958. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Pandey, G. Tuncman, G. S. Hotamisligil, and F. Samad Divergent Roles for p55 and p75 TNF-{alpha} Receptors in the Induction of Plasminogen Activator Inhibitor-1 Am. J. Pathol., March 1, 2003; 162(3): 933 - 941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. H. Lee, J. Giraud, R. J. Davis, and M. F. White c-Jun N-terminal Kinase (JNK) Mediates Feedback Inhibition of the Insulin Signaling Cascade J. Biol. Chem., January 24, 2003; 278(5): 2896 - 2902. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ruan, P. D. G. Miles, C. M. Ladd, K. Ross, T. R. Golub, J. M. Olefsky, and H. F. Lodish Profiling Gene Transcription In Vivo Reveals Adipose Tissue as an Immediate Target of Tumor Necrosis Factor-{alpha}: Implications for Insulin Resistance Diabetes, November 1, 2002; 51(11): 3176 - 3188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F. White IRS proteins and the common path to diabetes Am J Physiol Endocrinol Metab, September 1, 2002; 283(3): E413 - E422. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Peral, J. L. San Millan, R. Castello, P. Moghetti, and H. F. Escobar-Morreale The Methionine 196 Arginine Polymorphism in Exon 6 of the TNF Receptor 2 Gene (TNFRSF1B) Is Associated with the Polycystic Ovary Syndrome and Hyperandrogenism J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3977 - 3983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Valet, G. Tavernier, I. Castan-Laurell, J. S. Saulnier-Blache, and D. Langin Understanding adipose tissue development from transgenic animal models J. Lipid Res., June 1, 2002; 43(6): 835 - 860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ruan, N. Hacohen, T. R. Golub, L. Van Parijs, and H. F. Lodish Tumor Necrosis Factor-{alpha} Suppresses Adipocyte-Specific Genes and Activates Expression of Preadipocyte Genes in 3T3-L1 Adipocytes: Nuclear Factor-{kappa}B Activation by TNF-{alpha} Is Obligatory Diabetes, May 1, 2002; 51(5): 1319 - 1336. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Xu, J. Hirosumi, K. T. Uysal, A. D. Guler, and G. S. Hotamisligil Exclusive Action of Transmembrane TNF{alpha} in Adipose Tissue Leads to Reduced Adipose Mass and Local But Not Systemic Insulin Resistance Endocrinology, April 1, 2002; 143(4): 1502 - 1511. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Walczak and P. Tontonoz PPARadigms and PPARadoxes: expanding roles for PPAR{gamma} in the control of lipid metabolism J. Lipid Res., February 1, 2002; 43(2): 177 - 186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Togashi, N. Ura, K. Higashiura, H. Murakami, and K. Shimamoto Effect of TNF-{alpha}-Converting Enzyme Inhibitor on Insulin Resistance in Fructose-Fed Rats Hypertension, February 1, 2002; 39(2): 578 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Emanuelli, P. Peraldi, C. Filloux, C. Chavey, K. Freidinger, D. J. Hilton, G. S. Hotamisligil, and E. Van Obberghen SOCS-3 Inhibits Insulin Signaling and Is Up-regulated in Response to Tumor Necrosis Factor-alpha in the Adipose Tissue of Obese Mice J. Biol. Chem., December 14, 2001; 276(51): 47944 - 47949. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Fruhbeck, J. Gomez-Ambrosi, F. J. Muruzabal, and M. A. Burrell The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation Am J Physiol Endocrinol Metab, June 1, 2001; 280(6): E827 - E847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M.W. Geurts, R. G.J.H. Janssen, M. M.J. van Greevenbroek, C. J.H. van der Kallen, R. M. Cantor, X.-d. Bu, B. E. Aouizerat, H. Allayee, J. I. Rotter, and T. W.A. de Bruin Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia Hum. Mol. Genet., September 1, 2000; 9(14): 2067 - 2074. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Nisoli, L. Briscini, A. Giordano, C. Tonello, S. M. Wiesbrock, K. T. Uysal, S. Cinti, M. O. Carruba, and G. S. Hotamisligil Tumor necrosis factor alpha mediates apoptosis of brown adipocytes and defective brown adipocyte function in obesity PNAS, July 5, 2000; 97(14): 8033 - 8038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Xu, J. K. Sethi, and G. S. Hotamisligil Transmembrane Tumor Necrosis Factor (TNF)-alpha Inhibits Adipocyte Differentiation by Selectively Activating TNF Receptor 1 J. Biol. Chem., September 10, 1999; 274(37): 26287 - 26295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice The Insulin-Related Ovarian Regulatory System in Health and Disease Endocr. Rev., August 1, 1999; 20(4): 535 - 582. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Samad, K. T. Uysal, S. M. Wiesbrock, M. Pandey, G. S. Hotamisligil, and D. J. Loskutoff Tumor necrosis factor alpha is a key component in the obesity-linked elevation of plasminogen activator inhibitor 1 PNAS, June 8, 1999; 96(12): 6902 - 6907. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
