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Peroxisome proliferator activator receptor gamma coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation.
J Biol Chem. 2007 May 25; 282(21):15439-50.JB

Abstract

Peroxisome proliferator activator receptor-gamma 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-1alpha and -beta is reduced in both genetic (Lep(ob)/Lep(ob)) and acquired obesity (high fat diet). In C57BL6 mice, muscle PGC-1alpha expression decreased by 43% (p < 0.02) after 1 week of a high fat diet and persisted more than 11 weeks. In contrast, PGC-1alpha 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-1alpha and -beta mRNA expression. Palmitate decreased PGC-1alpha and -beta expression by 38% (p = 0.01) and 53% (p = 0.006); stearate similarly decreased expression of PGC-1alpha and -beta 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-1alpha 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-1alpha or -beta, 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 p38alpha 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.

Authors+Show Affiliations

Research Division, Joslin Diabetes Center, Division of Endocrinology, Department of Medicine and Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17416903

Citation

Crunkhorn, Sarah, et al. "Peroxisome Proliferator Activator Receptor Gamma Coactivator-1 Expression Is Reduced in Obesity: Potential Pathogenic Role of Saturated Fatty Acids and P38 Mitogen-activated Protein Kinase Activation." The Journal of Biological Chemistry, vol. 282, no. 21, 2007, pp. 15439-50.
Crunkhorn S, Dearie F, Mantzoros C, et al. Peroxisome proliferator activator receptor gamma coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation. J Biol Chem. 2007;282(21):15439-50.
Crunkhorn, S., Dearie, F., Mantzoros, C., Gami, H., da Silva, W. S., Espinoza, D., Faucette, R., Barry, K., Bianco, A. C., & Patti, M. E. (2007). Peroxisome proliferator activator receptor gamma coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation. The Journal of Biological Chemistry, 282(21), 15439-50.
Crunkhorn S, et al. Peroxisome Proliferator Activator Receptor Gamma Coactivator-1 Expression Is Reduced in Obesity: Potential Pathogenic Role of Saturated Fatty Acids and P38 Mitogen-activated Protein Kinase Activation. J Biol Chem. 2007 May 25;282(21):15439-50. PubMed PMID: 17416903.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Peroxisome proliferator activator receptor gamma coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation. AU - Crunkhorn,Sarah, AU - Dearie,Farrell, AU - Mantzoros,Christos, AU - Gami,Hiral, AU - da Silva,Wagner S, AU - Espinoza,Daniel, AU - Faucette,Ryan, AU - Barry,Kristen, AU - Bianco,Antonio C, AU - Patti,Mary Elizabeth, Y1 - 2007/04/06/ PY - 2007/4/10/pubmed PY - 2007/7/19/medline PY - 2007/4/10/entrez SP - 15439 EP - 50 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 282 IS - 21 N2 - Peroxisome proliferator activator receptor-gamma 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-1alpha and -beta is reduced in both genetic (Lep(ob)/Lep(ob)) and acquired obesity (high fat diet). In C57BL6 mice, muscle PGC-1alpha expression decreased by 43% (p < 0.02) after 1 week of a high fat diet and persisted more than 11 weeks. In contrast, PGC-1alpha 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-1alpha and -beta mRNA expression. Palmitate decreased PGC-1alpha and -beta expression by 38% (p = 0.01) and 53% (p = 0.006); stearate similarly decreased expression of PGC-1alpha and -beta 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-1alpha 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-1alpha or -beta, 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 p38alpha 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. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/17416903/Peroxisome_proliferator_activator_receptor_gamma_coactivator_1_expression_is_reduced_in_obesity:_potential_pathogenic_role_of_saturated_fatty_acids_and_p38_mitogen_activated_protein_kinase_activation_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&amp;pmid=17416903 DB - PRIME DP - Unbound Medicine ER -