Thiazolidinediones and Rexinoids Induce Peroxisome Proliferator-Activated Receptor-Coactivator (PGC)-1α Gene Transcription: An Autoregulatory Loop Controls PGC-1α Expression in Adipocytes via Peroxisome Proliferator-Activated Receptor-γ Coactivation

Hondares, Elayne; Mora, Ofelia; Yubero, Pilar; Concepción, Marisa Rodríguez de la; Iglesias, Roser; Giralt, Marta; Villarroya, Francesc

doi:10.1210/en.2006-0070

Cited by 164 publications

(129 citation statements)

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“…Indeed, the transcription of another MyoD target gene, UCP3, in which PGC-1␣ does not exert positive effects (11), is repressed by SIRT1. Moreover, the PGC-1␣-positive autoregulation of its own gene promoter has been previously reported and shown to be mediated by PPARs (25,26) or the myogenic factor MEF2C (5, 6), as also found in the present study. In light of the present findings, it could be hypothesized that other muscle genes that are targets of positive activation by MyoD and PGC-1␣ could be positively regulated by SIRT1.…”

Section: Discussionsupporting

confidence: 89%

SIRT1 Controls the Transcription of the Peroxisome Proliferator-activated Receptor-γ Co-activator-1α (PGC-1α) Gene in Skeletal Muscle through the PGC-1α Autoregulatory Loop and Interaction with MyoD

Amat

Planavila

Chen

et al. 2009

Journal of Biological Chemistry

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Peroxisome proliferator activated receptor-␥ co-activator-1␣ (PGC-1␣) is a transcriptional co-activator that coordinately regulates the expression of distinct sets of metabolism-related genes in different tissues. Here we show that PGC-1␣ expression is reduced in skeletal muscles from mice lacking the sirtuin family deacetylase SIRT1. Conversely, SIRT1 activation or overexpression in differentiated C2C12 myotubes increased PGC-1␣ mRNA expression. The transcription-promoting effects of SIRT1 occurred through stimulation of PGC-1␣ promoter activity and were enhanced by co-transfection of myogenic factors, such as myocyte enhancer factor 2 (MEF2) and, especially, myogenic determining factor (MyoD). SIRT1 bound to the proximal promoter region of the PGC-1␣ gene, an interaction potentiated by MEF2C or MyoD, which also interact with this region. In the presence of MyoD, SIRT1 promoted a positive autoregulatory PGC-1␣ expression loop, such that overexpression of PGC-1␣ increased PGC-1␣ promoter activity in the presence of co-expressed MyoD and SIRT1. Chromatin immunoprecipitation showed that SIRT1 interacts with PGC-1␣ promoter and increases PGC-1␣ recruitment to its own promoter region. Immunoprecipitation assays further showed that SIRT1-PGC-1␣ interactions are enhanced by MyoD. Collectively, these data indicate that SIRT1 controls PGC-1␣ gene expression in skeletal muscle and that MyoD is a key mediator of this action. The involvement of MyoD in SIRT1-dependent PGC-1␣ expression may help to explain the ability of SIRT1 to drive musclespecific gene expression and metabolism. Autoregulatory control of PGC-1␣ gene transcription seems to be a pivotal mechanism for conferring a transcription-activating response to SIRT1 in skeletal muscle.Peroxisome proliferator activated receptor-␥ co-activator-1␣ (PGC-1␣) 2 is a transcriptional co-activator that is recognized as a master controller of the expression of genes involved in metabolic regulation. PGC-1␣ exerts differential effects on metabolism in different tissues. In brown adipose tissue, PGC-1␣ increases the expression of uncoupling protein 1 and genes involved in mitochondrial oxidative pathways. In the liver, PGC-1␣ induces the expression of genes involved in gluconeogenesis and the metabolic response to starvation. In skeletal muscle, PGC-1␣ expression is rapidly induced by exercise in vivo (1), a response considered to be a mechanism for modulating metabolic flux in response to decreased ATP levels (2). Chronic exercise also increases PGC-1␣ expression in association with fiber-type switching toward the more oxidative and high endurance type IIa and type I fibers. The fiber-type switch promoted by PGC-1␣ is characterized by increased mitochondrial density and function, increased oxidative metabolism, increased expression of myofibrillar proteins characteristic of type I and type IIa muscle fibers and a switch in substrate fuel usage (3). Furthermore, greater levels of PGC-1␣ are found in oxidative fibers compared with glycolytic fibers, even in a rested state (3). Mo...

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Section: Discussionsupporting

confidence: 89%

SIRT1 Controls the Transcription of the Peroxisome Proliferator-activated Receptor-γ Co-activator-1α (PGC-1α) Gene in Skeletal Muscle through the PGC-1α Autoregulatory Loop and Interaction with MyoD

Amat

Planavila

Chen

et al. 2009

Journal of Biological Chemistry

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“…Here, we do not provide an explanation about how palmitate-mediated NF-B activation results in PGC-1␣ downregulation, but several mechanisms could be involved. Interestingly, while this study was under evaluation, Hondares et al (46) reported the presence of a PPAR␥ response element in the promoter of the PGC-1␣ gene. Since MEK activation decreases PPAR␥ activity by phosphorylating this nuclear receptor and/or by interfering its transactivation activity (47), this provides a potential mechanism for the MEKmediated downregulation of PGC-1␣ after palmitate exposure.…”

Section: Diabetes Vol 55 October 2006mentioning

confidence: 85%

Palmitate-Mediated Downregulation of Peroxisome Proliferator–Activated Receptor-γ Coactivator 1α in Skeletal Muscle Cells Involves MEK1/2 and Nuclear Factor-κB Activation

et al. 2006

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The mechanisms by which elevated levels of free fatty acids cause insulin resistance are not well understood. Previous studies have reported that insulin-resistant states are characterized by a reduction in the expression of peroxisome proliferator-activated receptor-␥ coactivator (PGC)-1, a transcriptional activator that promotes oxidative capacity in skeletal muscle cells. However, little is known about the factors responsible for reduced PGC-1 expression. The expression of PGC-1 mRNA levels was assessed in C2C12 skeletal muscle cells exposed to palmitate either in the presence or in the absence of several inhibitors to study the biochemical pathways involved. We report that exposure of C2C12 skeletal muscle cells to 0.75 mmol/l palmitate, but not oleate, reduced PGC-1␣ mRNA levels (66%; P < 0.001), whereas PGC-1␤ expression was not affected. Palmitate led to mitogen-activated protein kinase (MAPK)-extracellular signal-related kinase (ERK) 1/2 (MEK1/2) activation. In addition, pharmacological inhibition of this pathway by coincubation of the palmitate-exposed cells with the MEK1/2 inhibitors PD98059 and U0126 prevented the downregulation of PGC-1␣. Furthermore, nuclear factor-B (NF-B) activation was also involved in palmitatemediated PGC-1␣ downregulation, since the NF-B inhibitor parthenolide prevented a decrease in PGC-1␣ expression. These findings indicate that palmitate reduces PGC-1␣ expression in skeletal muscle cells through a mechanism involving MAPK-ERK and NF-B activation.

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“…Specifically, Pgc-1α is phosphorylated and thereby activated by p38 mitogenactivated protein kinase (MAPK) in response to sympathetic stimulation 102,103 . Activated Pgc-1α regulates the expression of thermogenic genes through its interactions with Ppar-γ, Ppar-α, thyroid receptor and other factors 96,104,105 , although a detailed mechanism to account for its selective effects at brown fat-specific genes is lacking. Pgc1a transcription also increases in response to β-adrenergic agonists through increases in the function of activating transcription factor-2 (Atf2) 102 .…”

Section: Sympathetic Nerve Control Of Brown and Beige Fatmentioning

confidence: 99%

Brown and beige fat: development, function and therapeutic potential

Harms

Seale

2013

Nat Med

1,992

2,054

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Adipose tissue, best known for its role in fat storage, can also suppress weight gain and metabolic disease through the action of specialized, heat-producing adipocytes. Brown adipocytes are located in dedicated depots and express constitutively high levels of thermogenic genes, whereas inducible 'brown-like' adipocytes, also known as beige cells, develop in white fat in response to various activators. The activities of brown and beige fat cells reduce metabolic disease, including obesity, in mice and correlate with leanness in humans. Many genes and pathways that regulate brown and beige adipocyte biology have now been identified, providing a variety of promising therapeutic targets for metabolic disease.npg

show abstract

Thiazolidinediones and Rexinoids Induce Peroxisome Proliferator-Activated Receptor-Coactivator (PGC)-1α Gene Transcription: An Autoregulatory Loop Controls PGC-1α Expression in Adipocytes via Peroxisome Proliferator-Activated Receptor-γ Coactivation

Cited by 164 publications

References 40 publications

SIRT1 Controls the Transcription of the Peroxisome Proliferator-activated Receptor-γ Co-activator-1α (PGC-1α) Gene in Skeletal Muscle through the PGC-1α Autoregulatory Loop and Interaction with MyoD

SIRT1 Controls the Transcription of the Peroxisome Proliferator-activated Receptor-γ Co-activator-1α (PGC-1α) Gene in Skeletal Muscle through the PGC-1α Autoregulatory Loop and Interaction with MyoD

Palmitate-Mediated Downregulation of Peroxisome Proliferator–Activated Receptor-γ Coactivator 1α in Skeletal Muscle Cells Involves MEK1/2 and Nuclear Factor-κB Activation

Brown and beige fat: development, function and therapeutic potential

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