HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 21, 15439-15450, May 25, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/21/15439    most recent M611214200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Crunkhorn, S. Articles by Patti, M. E. Search for Related Content PubMed PubMed Citation Articles by Crunkhorn, S. Articles by Patti, M. E. Social Bookmarking                      What's this?

Peroxisome Proliferator Activator Receptor Coactivator-1 Expression Is Reduced in Obesity

POTENTIAL PATHOGENIC ROLE OF SATURATED FATTY ACIDS AND p38 MITOGEN-ACTIVATED PROTEIN KINASE ACTIVATION^*

Sarah Crunkhorn, Farrell Dearie, Christos Mantzoros, Hiral Gami, Wagner S. da Silva, Daniel Espinoza, Ryan Faucette, Kristen Barry, Antonio C. Bianco, and Mary Elizabeth Patti¹

From the Research Division, Joslin Diabetes Center, Division of Endocrinology, Department of Medicine and Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215 and Thyroid Section, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Peroxisome proliferator activator receptor- coactivator 1 (PGC-1) is a major candidate gene for diabetes-related metabolic phenotypes, contributing to decreased expression of nuclear-encoded mitochondrial genes in muscle and adipose tissue. We have demonstrated that muscle expression of PGC-1 and - is reduced in both genetic (Lep^ob/Lep^ob) and acquired obesity (high fat diet). In C57BL6 mice, muscle PGC-1 expression decreased by 43% (p < 0.02) after 1 week of a high fat diet and persisted more than 11 weeks. In contrast, PGC-1 reductions were not sustained in obesity-resistant A/J mice. To identify mediators of obesity-linked reductions in PGC-1, we tested the effects of cellular nutrients in C2C12 myotubes. Although overnight exposure to high insulin, glucose, glucosamine, or amino acids had no effect, saturated fatty acids potently reduced PGC-1 and - mRNA expression. Palmitate decreased PGC-1 and - expression by 38% (p = 0.01) and 53% (p = 0.006); stearate similarly decreased expression of PGC-1 and - by 22% (p = 0.02) and 39% (p = 0.02). These effects were mediated at a transcriptional level, as indicated by an 11-fold reduction of PGC-1 promoter activity by palmitate and reversal of effects by histone deacetylase inhibition. Palmitate also (a) reduced expression of tricarboxylic acid cycle and oxidative phosphorylation mitochondrial genes and (b) reduced oxygen consumption. These effects were reversed by overexpression of PGC-1 or -, indicating PGC-1 dependence. Palmitate effects also required p38 MAPK, as demonstrated by 1) palmitate-induced increase in p38 MAPK phosphorylation, 2) reversal of palmitate effects on PGC-1 and mitochondrial gene expression by p38 MAPK inhibitors, and 3) reversal of palmitate effects by small interfering RNA-mediated decreases in p38 MAPK. These data indicate that obesity and saturated fatty acids decrease PGC-1 and mitochondrial gene expression and function via p38 MAPK-dependent transcriptional pathways.

Received for publication, December 6, 2006 , and in revised form, April 3, 2007.

^* This work was supported by National Institutes of Health Grants DK062948 and DK060837 (to M. E. P.), DK65055 (to A. C. B.), and DK36836 (to the Diabetes and Endocrinology Research Center, Joslin Diabetes Center). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3 and Tables 1 and 2.

¹ To whom correspondence should be addressed: Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA 02215. Tel.: 617-735-1966; Fax: 617-732-2593; E-mail: mary.elizabeth.patti{at}joslin.harvard.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Muraoka, A. Fukushima, S. Viengchareun, M. Lombes, F. Kishi, A. Miyauchi, M. Kanematsu, J. Doi, J. Kajimura, R. Nakai, et al. Involvement of SIK2/TORC2 signaling cascade in the regulation of insulin-induced PGC-1{alpha} and UCP-1 gene expression in brown adipocytes Am J Physiol Endocrinol Metab, June 1, 2009; 296(6): E1430 - E1439. [Abstract] [Full Text] [PDF]

				X. Palomer, D. Alvarez-Guardia, R. Rodriguez-Calvo, T. Coll, J. C. Laguna, M. M. Davidson, T. O. Chan, A. M. Feldman, and M. Vazquez-Carrera TNF-{alpha} reduces PGC-1{alpha} expression through NF-{kappa}B and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model Cardiovasc Res, March 1, 2009; 81(4): 703 - 712. [Abstract] [Full Text] [PDF]

				J. O Holloszy Skeletal muscle "mitochondrial deficiency" does not mediate insulin resistance Am. J. Clinical Nutrition, January 1, 2009; 89(1): 463S - 466S. [Abstract] [Full Text] [PDF]

				A. Kennedy, K. Martinez, C.-C. Chuang, K. LaPoint, and M. McIntosh Saturated Fatty Acid-Mediated Inflammation and Insulin Resistance in Adipose Tissue: Mechanisms of Action and Implications J. Nutr., January 1, 2009; 139(1): 1 - 4. [Abstract] [Full Text] [PDF]

				M. W. Ruddock, A. Stein, E. Landaker, J. Park, R. C. Cooksey, D. McClain, and M.-E. Patti Saturated Fatty Acids Inhibit Hepatic Insulin Action by Modulating Insulin Receptor Expression and Post-receptor Signalling J. Biochem., November 1, 2008; 144(5): 599 - 607. [Abstract] [Full Text] [PDF]

				L. N. Sutherland, L. C. Capozzi, N. J. Turchinsky, R. C. Bell, and D. C. Wright Time course of high-fat diet-induced reductions in adipose tissue mitochondrial proteins: potential mechanisms and the relationship to glucose intolerance Am J Physiol Endocrinol Metab, November 1, 2008; 295(5): E1076 - E1083. [Abstract] [Full Text] [PDF]

				P. Lau, R. L. Fitzsimmons, S. Raichur, S.-C. M. Wang, A. Lechtken, and G. E. O. Muscat The Orphan Nuclear Receptor, ROR{alpha}, Regulates Gene Expression That Controls Lipid Metabolism: STAGGERER (SG/SG) MICE ARE RESISTANT TO DIET-INDUCED OBESITY J. Biol. Chem., June 27, 2008; 283(26): 18411 - 18421. [Abstract] [Full Text] [PDF]

				C. R. Hancock, D.-H. Han, M. Chen, S. Terada, T. Yasuda, D. C. Wright, and J. O. Holloszy High-fat diets cause insulin resistance despite an increase in muscle mitochondria PNAS, June 3, 2008; 105(22): 7815 - 7820. [Abstract] [Full Text] [PDF]