Sarah Crunkhorn

Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic beta cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. To identify genes potentially important in the pathogenesis of DM, we analyzed gene expression in skeletal muscle from healthy metabolically characterized nondiabetic (family history negative and positive for DM) and diabetic Mexican-American subjects. We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. Although NRF-1 expression is decreased only in diabetic subjects, expression of both PPAR gamma coactivator 1-alpha and-beta (PGC1-alpha/PPARGC1 and PGC1-beta/PERC), coactivators of NRF-1 and PPAR gamma-dependent transcription, is decreased in both diabetic subjects and family history-positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.

Peroxisome proliferator activator receptor-γ 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-1α and -β is reduced in both genetic (Lepob/Lepob) and acquired obesity (high fat diet). In C57BL6 mice, muscle PGC-1α expression decreased by 43% (p < 0.02) after 1 week of a high fat diet and persisted more than 11 weeks. In contrast, PGC-1α 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-1α and -β mRNA expression. Palmitate decreased PGC-1α and -β expression by 38% (p = 0.01) and 53% (p = 0.006); stearate similarly decreased expression of PGC-1α and -β 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-1α 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-1α or -β, 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 p38α 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. Peroxisome proliferator activator receptor-γ 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-1α and -β is reduced in both genetic (Lepob/Lepob) and acquired obesity (high fat diet). In C57BL6 mice, muscle PGC-1α expression decreased by 43% (p < 0.02) after 1 week of a high fat diet and persisted more than 11 weeks. In contrast, PGC-1α 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-1α and -β mRNA expression. Palmitate decreased PGC-1α and -β expression by 38% (p = 0.01) and 53% (p = 0.006); stearate similarly decreased expression of PGC-1α and -β 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-1α 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-1α or -β, 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 p38α 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. The earliest detectable abnormalities in subjects at risk for developing type 2 diabetes (DM) 2The abbreviations used are: DM, type 2 diabetes; BSA, bovine serum albumin; PPAR, peroxisome proliferator activator receptor; PGC-1, PPAR-γ coactivator-1; ACC, acetyl-coA carboxylase; AICAR, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside; mTOR, mammalian target of rapamycin; MEF2, MADS Box transcription enhancer factor 2; NF-κB, nuclear factor κB; MAPK, mitogen-activated protein kinase; siRNA, small interfering RNA; FA, fatty acid(s); FFA, free fatty acid(s).2The abbreviations used are: DM, type 2 diabetes; BSA, bovine serum albumin; PPAR, peroxisome proliferator activator receptor; PGC-1, PPAR-γ coactivator-1; ACC, acetyl-coA carboxylase; AICAR, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside; mTOR, mammalian target of rapamycin; MEF2, MADS Box transcription enhancer factor 2; NF-κB, nuclear factor κB; MAPK, mitogen-activated protein kinase; siRNA, small interfering RNA; FA, fatty acid(s); FFA, free fatty acid(s). are insulin resistance and accumulation of lipid in skeletal muscle (1Eriksson J. 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Recent genomic and functional studies of muscle from humans with diabetes or at high risk for diabetes have demonstrated that impairments in nuclear-encoded mitochondrial gene expression and function are a key signature of diabetes (5Patti M.E. Butte A.J. Crunkhorn S. Cusi K. Berria R. Kashyap S. Miyazaki Y. Kohane I. Costello M. Saccone R. Landaker E.J. Goldfine A.B. Mun E. DeFronzo R. Finlayson J. Kahn C.R. Mandarino L.J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, A. S. J. E. M. E. N. N. J.P. Groop PubMed Scopus Google Scholar, K. S. J. N. S. S. S. M. J. PubMed Scopus Google Scholar, S. R. N. Engl. J. Med. PubMed Scopus Google Scholar, J. Diabetes. PubMed Scopus Google Scholar). the increase in DM, is to the genetic and transcriptional mitochondrial PGC-1α coactivator and are as key of mitochondrial and function via with nuclear factor and nuclear and transcription C. PubMed Scopus Google Scholar). expression of both PGC-1α and -β is reduced by in skeletal muscle from and humans (5Patti M.E. Butte A.J. Crunkhorn S. Cusi K. Berria R. Kashyap S. Miyazaki Y. Kohane I. Costello M. Saccone R. Landaker E.J. Goldfine A.B. Mun E. DeFronzo R. Finlayson J. Kahn C.R. Mandarino L.J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google PGC-1 as a candidate gene diabetes-related metabolic In both genetic and to reduced expression of PGC-1α and -β in in PGC-1 have with obesity and diabetes H. R. K. M. F. W. Diabetes. PubMed Scopus Google Scholar, C. E. M. J. H. Groop L. A. J. PubMed Scopus Google Scholar, H. H. M. F. W. Diabetes. PubMed Scopus Google Scholar). We that PGC-1 also the effects of risk and the of in the of insulin resistance and insulin PGC-1α expression in skeletal muscle of subjects Vidal H. Andreelli F. Laville M. J. 1999; PubMed Scopus Google Scholar). muscle expression of PGC-1α in both humans and S. I. J. PubMed Scopus Google Scholar, H. J. Scopus Google Scholar). of decreases expression of PGC-1α and nuclear-encoded mitochondrial genes Kashyap S. M. Cusi K. Mandarino Finlayson J. DeFronzo Mandarino L.J. J. PubMed Scopus Google Scholar). high fat in humans also in decreased PGC-1α and mitochondrial gene expression in skeletal muscle after H. R. Diabetes. PubMed Scopus Google Scholar). Although and PGC-1 expression have the precise effects We a for saturated fatty acids to both PGC-1α and gene expression and mitochondrial gene expression and oxidative function at a transcriptional level, mediated via p38 MAPK-dependent pathways. and acids were from from and were from and from by amino acid with amino acids were from were from The expression the gene with a of the of the PGC-1α gene to to transcriptional and for and and were by J. R. J. J. PubMed Scopus Google Scholar). and were in an of with a were by the and and were from The of were on from or high fat diet from and from 1 to 11 and A/J = or from 1 to = or = were with or with for In insulin by insulin with at and were with muscle and in and from or C2C12 with for were and to protein expression. were are in C2C12 were in with bovine serum at a of To were to and to serum and 2 with and at and from in and were a were by for were for 1 in in with with at for 1 and acids were in at for 2 and with fatty BSA, a of H. 2001; PubMed Scopus Google Scholar). and were with and gene expression on of were with palmitate or on and and and activity the and activity to as from C2C12 overnight with palmitate or BSA, and = of to were used to expression data with pathways. of PGC-1α and were in in with C2C12 were at 2 of with of to for 2 more as and on for for and genes and to the are in were in of were with palmitate or for or were a M. C. H. N. K. J. PubMed Scopus Google Scholar). were at were to protein after of were at of with p38α MAPK, or or were overnight with palmitate or on of and and protein were on of and of by of PGC-1 in in of genetic or obesity to decreased expression of PGC-1 and mitochondrial gene expression. In the expression decreased by (p < in muscle as with were for PGC-1α = These were also in muscle with C57BL6 in C57BL6 obesity after 2 of a high fat both PGC-1α and expression decreased in by (p = 0.01) and (p = as with reduced PGC-1α expression in C57BL6 as as 1 week after of a high fat diet and an and with expression with = = and insulin = = 0.02) at 11 weeks. In contrast, muscle from obesity-resistant A/J an reduction in PGC-1α expression reduction at 1 = this not sustained the of also decreased in C57BL6 reduction at 11 = not in PGC-1α and expression in both genetic and obesity that obesity metabolic insulin and cellular to in humans with insulin resistance and type 2 diabetes (5Patti M.E. Butte A.J. Crunkhorn S. Cusi K. Berria R. Kashyap S. Miyazaki Y. Kohane I. Costello M. Saccone R. Landaker E.J. Goldfine A.B. Mun E. DeFronzo R. Finlayson J. Kahn C.R. Mandarino L.J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, A. S. J. E. M. E. N. N. J.P. Groop PubMed Scopus Google Scholar, H. R. Diabetes. PubMed Scopus Google Scholar). and on PGC-1 the cellular effects of sustained exposure to high insulin in the of metabolic of C2C12 overnight with insulin to in the of serum no in mRNA expression of PGC-1α or -β of insulin resistance by overnight with the had no on expression of PGC-1α the of insulin resistance as demonstrated by decreased phosphorylation with 1 for or with 1 factor for both of insulin resistance in not PGC-1 and resistance are key of genetic and we also tested the effects of on PGC-1 expression in myotubes. had a of PGC-1 expression in C2C12 < of the of both humans and mice, is with reduced expression of mitochondrial genes R. Diabetes. PubMed Scopus Google Scholar). To in reductions in PGC-1 C2C12 were overnight with or high in the or of insulin to of PGC-1α or -β not as a function of exposure of to high had no The is a in the of both and insulin of this by decreases expression of nuclear-encoded mitochondrial genes in skeletal muscle S. J. R. U. K. L. J. PubMed Scopus Google Scholar). tested of the PGC-1 expression. with not PGC-1α or -β expression in the or of insulin on PGC-1 high of amino insulin resistance via of the F. H. A. PubMed Scopus Google Scholar). with of PGC-1 expression and are to high fat of insulin resistance and obesity F. M. F. M. M. S. J. PubMed Scopus Google Scholar). In no of amino acids that in on expression of PGC-1 acids have as of insulin resistance PubMed Scopus Google Scholar, A. M. M.E. S. J. 1999; PubMed Scopus (999) Google Scholar). we C2C12 overnight with saturated and FA, acid acid acid acid acid and acid and the fatty acid or with Although and fatty acids in to had no on PGC-1 and saturated fatty acids potently decreased expression of both PGC-1α and Palmitate decreased expression of both PGC-1α and -β by 38% (p = 0.01) and 53% (p = stearate similarly decreased expression of both PGC-1α = 0.02) and = 0.02) this of palmitate insulin resistance as demonstrated by decreased phosphorylation were in the of palmitate and or no decrease in PGC-1 expression of PGC-1 expression by and C2C12 with 2 or 2 with palmitate of PGC-1α and by and of with or 2 or palmitate are the The < for the of or as with < for effects in the of of fatty acids are in with obesity and with C. Diabetes. PubMed Scopus Google Scholar). Although fatty acid is this we that a of fatty acid H. N. F. A. Haring H.U. PubMed Scopus Google Scholar). more of palmitate also decreased PGC-1α expression = = not and a from to of exposure Palmitate as a saturated for of with palmitate palmitate that a had no on PGC-1 mRNA that of a fatty is for inhibition. of with of required for of from the to the the effects of palmitate to decrease PGC-1 expression not Palmitate PGC-1α in PGC-1 mRNA expression transcription or To the of palmitate on PGC-1 promoter we C2C12 with the gene with a of the of the PGC-1α gene and a expression were at of with palmitate or palmitate decreased PGC-1α mRNA expression by (p = and decreased PGC-1α activity by 11-fold (p < Palmitate and of data from C2C12 overnight with palmitate decreased expression of mitochondrial of the tricarboxylic acid cycle = < and = < 2) as with We expression of tricarboxylic acid cycle and genes by 2 = = = mitochondrial = and the 1 = we no in mitochondrial of palmitate To the effects on mitochondrial we oxygen after palmitate exposure Although we a increase at oxygen decreased by of palmitate exposure = Palmitate on and the PGC-1 of the effects of palmitate on oxidative gene expression and both and overexpression PGC-1α -β expression by and decreased expression of tricarboxylic acid cycle and oxidative phosphorylation < for overexpression of PGC-1α or protein of a oxidative phosphorylation PGC-1 the of palmitate on expression indicating that palmitate-induced effects on mitochondrial gene expression are mediated by In fatty acids that not expression of PGC-1 and not expression of overexpression of PGC-1α or -β also reversed the of palmitate to decrease oxygen at and PGC-1 were with or AICAR, a activator of protein is a key by N. N. I. S. A. L.J. Diabetes. 2001; 50: PubMed Scopus Google Scholar). and PGC-1α expression by (p < and (p < To the of palmitate on PGC-1 were for with palmitate or and PGC-1α expression in the of palmitate by and (p < for and both and reversed the of palmitate expression of by (p = and reversed the of palmitate also expression in with palmitate by (p = These in PGC-1 expression in with insulin as by phosphorylation the effects of to increase Y. C. Kahn PubMed Scopus Google and of to palmitate Although data a of protein to effects M. H. H. S. J. PubMed Scopus Google Scholar, N. A.J. E. Diabetes. PubMed Scopus Google Scholar, J. J. S. 2001; PubMed Scopus Google this as we no of palmitate on phosphorylation of protein or in the or in To the effects of and on PGC-1 expression also to the in we or with or for PGC-1α mRNA expression by (p = and by (p = 0.01) in 3) in with in insulin also PGC-1α expression in high by (p = not were for in mice, PGC-1α by 53% (p = and by (p = had no on PGC-1 expression in the of of transcription the of We a reversal of palmitate effects with the histone deacetylase PGC-1α expression by (p < and in by (p = These a for histone in the effects of palmitate on PGC-1 expression J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). To the the effects of we C2C12 with the of palmitate and the effects on palmitate-induced decreases in PGC-1α mRNA expression or promoter were on (a) on expression activity of to PGC-1 (b) by fatty to insulin We no of (a) of the S. J. R. U. K. L. J. PubMed Scopus Google or the F. M. F. M. M. S. J. PubMed Scopus Google and no in phosphorylation of or (b) of of of fatty acid with insulin resistance Berria R. E. DeFronzo Mandarino L.J. Diabetes. PubMed Scopus Google of M. F. C. A. W. PubMed Scopus Google or and no in expression of nuclear of PubMed Scopus Google and no in expression of of protein Y. C. Y. M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google or phosphorylation C. PubMed Scopus Google of to by fatty acids and in humans with diabetes M. K. N. Diabetes. PubMed Scopus Google Scholar, A. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google and PubMed Scopus Google Scholar). Although reversed palmitate of oxidative genes 1 and (p = and (p = 0.02) not expression of and protein are to expression of PGC-1α by of the transcription protein and J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, Y. C. Y. M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, C. J. J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). Although we no of the expression of and decreased by In decreased not of p38 MAPK-dependent in Palmitate also to of PGC-1 J. J. S. 2001; PubMed Scopus Google Scholar, A. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar, M. R. E. M. M. Diabetes. PubMed Scopus Google Scholar). or were in palmitate Palmitate exposure increase p38 MAPK phosphorylation from to this by with the MAPK data are at 1 palmitate-induced decreases in PGC-1 expression effects were with 2 MAPK inhibitors, and contrast, no of or The p38 MAPK also palmitate-induced decreases in and mRNA expression of p38 MAPK the effects of palmitate on PGC-1 and mitochondrial gene expression in C2C12 myotubes. of p38 MAPK phosphorylation in C2C12 for 1 with or palmitate in the or of mRNA expression of PGC-1α and -β, and in C2C12 with palmitate for in the or of p38 MAPK or of or on PGC-1α mRNA expression. and from C2C12 on of with of p38α siRNA, as demonstrated by and and p38 of p38α to palmitate-induced p38α of p38α on palmitate-induced reductions in PGC-1α and -β and mRNA expression. are the < < are we with p38α MAPK and overnight with palmitate or a of p38α MAPK reduced by (p = 0.02) at the and at the protein (p = and phosphorylation of p38 MAPK reduced by (p = this reduction in p38α MAPK both palmitate-induced phosphorylation of p38 MAPK and palmitate-induced reductions in and mRNA expression a for p38 MAPK-dependent in the effects of of the that mitochondrial is a key of insulin resistance and type 2 diabetes K. S. J. N. S. S. S. M. J. PubMed Scopus Google Scholar, S. R. N. Engl. J. Med. PubMed Scopus Google and to reduced lipid accumulation of lipid S. Machann J. Rett K. Brechtel K. Volk A. Renn W. Maerker E. Matthaei S. Schick F. Claussen C.D. Haring H.U. Diabetes. 1999; 48: 1113-1119Crossref PubMed Scopus (543) Google and of insulin resistance L. I. H. Diabetes. PubMed Scopus Google Scholar). We that genetic and risk decrease expression of PGC-1α and and mitochondrial gene expression and function J. M.E. and in and Scholar). In studies expression of PGC-1α and -β reduced in skeletal muscle from with genetic or These data are in with the that muscle expression of PGC-1 and mitochondrial genes is decreased in humans after of high fat diet H. R. Diabetes. 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J. and 2 Diabetes. data not a for the or in palmitate effects on of and also a We a of to increase PGC-1 expression in that in or resistance with high fat to in PGC-1 expression in at a cellular level, of were to the effects of both and were in mice. we a of resistance in palmitate effects on PGC-1 resistance is to a major also to insulin and mitochondrial S. M. DeFronzo Mandarino L. E. PubMed Scopus Google Scholar). in C57BL6 high fat PGC-1 were is that a in this in we a of resistance in this of of palmitate had no on PGC-1 that a fatty or is for effects on PGC-1 expression. of palmitate effects by also that a mitochondrial oxidative or effects PubMed Scopus Google Scholar). We no of of Berria R. E. DeFronzo Mandarino L.J. Diabetes. PubMed Scopus Google Scholar). candidate fatty acid in oxygen PubMed Scopus Google Scholar). fat oxidative in muscle R. J. A. J. J. R. J. PubMed Scopus Google and PGC-1 the effects of oxygen J. S. M. J. S. C. K. J. W. R. PubMed Scopus Google Scholar). 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S. 2001; PubMed Scopus Google the palmitate-induced reduction in mitochondrial gene expression and function and reversal by p38 MAPK that palmitate also PGC-1 transcriptional data with a in to decreases in we no of or M. R. E. M. M. Diabetes. PubMed Scopus Google Scholar). in of PGC-1α transcriptional a that reversed by p38 MAPK phosphorylation M. J. J. C. J. S. H. PubMed Scopus Google Scholar). Although expression by palmitate = not we no of on PGC-1 expression or transcriptional activity on mitochondrial or p38 MAPK expression not not to palmitate effects in this data that sustained of p38 MAPK as a transcriptional of both PGC-1α and and mitochondrial gene expression. effects of sustained p38 MAPK also both and with the pathways. In this is that p38 MAPK phosphorylation is in from type 2 in with decreased and S. Diabetes. PubMed Scopus Google Scholar). In high fat in p38 MAPK phosphorylation in Y. A. J. PubMed Scopus Google and p38 is with insulin resistance Y. F. W. J. PubMed Scopus Google Scholar). of p38α MAPK also effects in the J. M. Y. H. H. PubMed Scopus Google Scholar). to high fat similarly to p38 MAPK activity in In we that sustained cellular exposure to saturated expression of PGC-1α and -β and mitochondrial oxidative gene expression and cellular oxygen to oxidative or accumulation of of with reductions in PGC-1 with and fatty acid and metabolic and insulin We that the precise effects of and palmitate-induced decreases in PGC-1 expression on insulin and in skeletal muscle remains unknown. Although PGC-1α in decreases mitochondrial gene expression and in skeletal muscle J. P.H. J. S. C.R. L. M. S. PubMed Scopus Google are from to in activity with C.R. M. R. J. S. I. S. PubMed Scopus Google Scholar, N. A. M. N. K. M. S. M. M. M. A. Y. L. M. M. M. A. PubMed Scopus Google Scholar, J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google decreases mitochondrial gene expression not insulin J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). and of PGC-1α in required to the of muscle PGC-1 on skeletal muscle insulin In saturated fatty acids decreased expression of and oxidative phosphorylation genes as well as mitochondrial function These effects to mediated at a transcriptional via of fatty acid and p38 MAPK with insulin and of histone deacetylase and p38 to skeletal muscle metabolic with insulin resistance and with

A key phenotype associated with type 2 diabetes in humans is impaired mitochondrial oxidative metabolism in skeletal muscle, a pattern potentially contributing to increased lipid accumulation and impaired metabolic flexibility-in turn, central features of both insulin resistance and diabetes. Since thyroid hormone regulates mitochondrial gene expression and function in skeletal muscle, reductions in T3-mediated transcription may contribute to diabetes-related impairments in oxidative metabolism. We review the evidence for relationships between thyroid hormone action and diabetes risk, and discuss potential mechanisms linking intracellular thyroid hormone availability, thyroid receptor action, and the transcriptional coactivator PGC1 in regulating oxidative metabolism.