Research Notes: PPARgamma coactivator-1alpha (PGC-1alpha)

J Clin Invest. 2007 Oct 11.
Abnormal glucose homeostasis in skeletal muscle-specific PGC-1alpha knockout mice reveals skeletal muscle-pancreatic beta cell crosstalk.
Handschin C, Choi CS, Chin S, Kim S, Kawamori D, Kurpad AJ, Neubauer N, Hu J, Mootha VK, Kim YB, Kulkarni RN, Shulman GI, Spiegelman BM.
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. Howard Hughes Medical Institute and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA. Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Center for Human Genetic Research, Massachusetts General Hospital, and Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA. Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.

The transcriptional coactivator PPARgamma coactivator 1alpha (PGC-1alpha) is a strong activator of mitochondrial biogenesis and oxidative metabolism. While expression of PGC-1alpha and many of its mitochondrial target genes are decreased in the skeletal muscle of patients with type 2 diabetes, no causal relationship between decreased PGC-1alpha expression and abnormal glucose metabolism has been established. To address this question, we generated skeletal muscle-specific PGC-1alpha knockout mice (MKOs), which developed significantly impaired glucose tolerance but showed normal peripheral insulin sensitivity. Surprisingly, MKOs had expanded pancreatic beta cell mass, but markedly reduced plasma insulin levels, in both fed and fasted conditions. Muscle tissue from MKOs showed increased expression of several proinflammatory genes, and these mice also had elevated levels of the circulating IL-6. We further demonstrated that IL-6 treatment of isolated mouse islets suppressed glucose-stimulated insulin secretion. These data clearly illustrate a causal role for muscle PGC-1alpha in maintenance of glucose homeostasis and highlight an unexpected cytokine-mediated crosstalk between skeletal muscle and pancreatic islets.

Adv Physiol Educ. 2006 Dec.
PGC-1alpha: a key regulator of energy metabolism.
Liang H, Ward WF.
Department of Cellular and Structural Biology, Audie Murphy Veterans Administration Medical Center and University of Texas Health Science Center, San Antonio, Texas, USA.
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Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha is a member of a family of transcription coactivators that plays a central role in the regulation of cellular energy metabolism. It is strongly induced by cold exposure, linking this environmental stimulus to adaptive thermogenesis. PGC-1alpha stimulates mitochondrial biogenesis and promotes the remodeling of muscle tissue to a fiber-type composition that is metabolically more oxidative and less glycolytic in nature, and it participates in the regulation of both carbohydrate and lipid metabolism. It is highly likely that PGC-1alpha is intimately involved in disorders such as obesity, diabetes, and cardiomyopathy. In particular, its regulatory function in lipid metabolism makes it an inviting target for pharmacological intervention in the treatment of obesity and Type 2 diabetes.

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Skeletal muscle fibers are classified into three types: type I, type IIa, and type IIb. Slow-twitch type I and fast-twitch type IIa fibers contain more mitochondria and exhibit relatively higher rates of oxidative metabolism. In contrast, type IIb fibers have fewer mitochondria and are metabolically glycolytic. It is now well established that PGC-1 induces a remodeling of skeletal muscle fiber composition. In general, the ratio of glycolytic type IIb fibers to the more oxidative type I and type IIa fibers decreases. The expression of PGC-1 in skeletal muscle is readily inducible by both short-term exercise and endurance training in rodent models and human subjects (5, 15, 41, 52). Our understanding of the biological role of PGC-1 in skeletal muscle structure and function has been greatly improved through the use of gain of function and loss of function mouse models. In a gain of function transgenic model, PGC-1 is overexpressed in a skeletal muscle-specific manner under the control of the muscle creatine kinase (MCK) promoter (28). PGC-1 overexpression results in the conversion of fast-twitch type IIb muscle fibers to type IIa and slow-twitch type I fibers by 20% and 10%, respectively, in plantaris muscle. In addition, there is an activation of genes involved in mitochondrial oxidative metabolism. The conversion to slow-twitch fibers is also evidenced by the redder muscle color and the expression of contractile proteins characteristic of slow-twitch fibers such as slow troponin I and myoglobin. As would be predicted, based on these alterations, muscles isolated from the MCK-PGC-1 transgenic mouse show increased resistance to electrically stimulated fatigue (28). Consistent with this, Mortenson et al. (39) recently reported that overexpression of PGC-1 in primary rat skeletal muscle cells leads to enhanced levels of mRNA for the slow oxidative-associated myosin heavy chain (MHC) isoform (MHCIb) and decreased mRNA levels for the fast glycolytic-associated MHC isoforms (MHCIIX and MHCIIB) (39). In contrast, PGC-1-deficient mice exhibit decreased mitochondrial number and decreased respiratory capacity in slow-twitch muscle as well as reduced exercise capacity and a reduced fatigue resistance index (26).

Am J Physiol Endocrinol Metab. 2006 Oct.
PGC-1alpha and PGC-1beta have both similar and distinct effects on myofiber switching toward an oxidative phenotype.
Mortensen OH, Frandsen L, Schjerling P, Nishimura E, Grunnet N.
Department of Medical Biochemistry and Genetics, University of Copenhagen, Blegdamsvej 3, Bldg. 6.5, DK-2200 N, Denmark.
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Peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -1beta (PGC-1alpha and PGC-1beta) were overexpressed by adenovirus-mediated gene transfer in cultures of primary rat skeletal muscle cells derived from neonatal myoblasts. Effects on muscle fiber type transition and metabolism were studied from days 5 to 22 of culture. PGC-1alpha and PGC-1beta overexpression caused a three- to fourfold increase in mRNA level, a doubling of enzymatic activity of citrate synthase, a slight increase in short-chain acyl-CoA dehydrogenase mRNA, a doubling of the mRNA level, and a 30-50% increase in enzymatic activity of glyceraldehyde-3-phosphate dehydrogenase. Lactate dehydrogenase or creatine kinase activity was unchanged. PGC-1alpha enhanced glycogen buildup twofold at 5 or 25 mM glucose, whereas PGC-1beta caused a decrease. Both PGC-1alpha and PGC-1beta overexpression caused a faster maturation of myotubes, as seen by mRNA downregulation of the immature embryonal and perinatal myosin heavy-chain (MHC) isoforms. PGC-1alpha or PGC-1beta overexpression enhanced mRNA of the slow oxidative-associated MHC isoform MHCIb and downregulated mRNA levels of the fast glycolytic-associated MHC isoforms MHCIIX and MHCIIB. Only PGC-1beta overexpression caused an increase in mRNA of the intermediary fast oxidative-associated MHC isoform MHCIIA. PGC-1alpha or PGC-1beta overexpression upregulated GLUT4 mRNA and downregulated myocyte enhancer factor 2C transcription factor mRNA; only PGC-1alpha overexpression caused an increase in the mRNA expression of TRB3, a negative regulator of insulin signaling. These results show that both PGC-1alpha and PGC-1beta are involved in the regulation of skeletal muscle fiber transition and metabolism and that they have both overlapping and differing effects.

Endocrinology. 2006 Feb.
Role of peroxisome proliferator-activated receptor-gamma coactivator-1alpha in the transcriptional regulation of the human uncoupling protein 2 gene in INS-1E cells.
Oberkofler H, Klein K, Felder TK, Krempler F, Patsch W.
Department of Laboratory Medicine, Landeskliniken and Paracelsus Private Medical University Salzburg, Austria.
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A role of uncoupling protein 2 (UCP2) as negative modulator of insulin secretion has been suggested, but the transcriptional pathways regulating beta-cell UCP2 gene expression have been established in rodents only. We show here that the underlying sequence motifs are not conserved in the human gene and provide evidence for regulatory mechanisms involving the transcriptional cofactor peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1alpha). PGC-1alpha potentiates thyroid hormone (T(3))-mediated transcriptional activation of the human UCP2 gene in INS-1E cells. Two thyroid hormone response elements (TREs) located at -322/-317 (TRE1) and -170/-165 (TRE2) were identified, and mutation of either TRE1 or TRE2 abrogated the stimulatory effect of T(3) treatment. Furthermore, two E-box motifs at -911/-906 (E1) and -743/-738 (E2) are involved in the regulation of UCP2 gene expression by sterol regulatory element binding protein isoforms (SREBP)-1a, -1c, and -2. Mutational analysis revealed that the presence of either E1 or E2 is sufficient to mediate activation of UCP2 gene transcription by nuclear active SREBPs. PGC-1alpha coactivates liver X receptor-mediated expression of SREBP-1c as well as dexamethasone-stimulated SREBP-2 expression in INS-1E cells. These transcriptional responses are antagonized by orphan nuclear receptor short heterodimer partner overexpression, which might explain its positive effects on glucose-stimulated insulin secretion in beta-cells overexpressing UCP2. We also provide evidence that despite a lack of sequence homology within the regulatory region, the principal mechanisms regulating UCP2 gene expression are similar in rats and humans, being consistent with a role for UCP2 as a modulator of insulin secretion in humans.

Med Sci (Paris). 2005 Jan.
PGC-1alpha, a transcriptional coactivator involved in metabolism. [Article in French]
Tiraby C, Langin D.
Unité de recherches sur les obésités, Inserm UPS U.586, Institut Louis-Bugnard, CHU de Rangueil, 1, avenue Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9, France.

Transcriptional coactivators can be important targets for physiologic regulation. PPARgamma coactivator-1alpha (PGC-1alpha), in cooperation with several transcription factors, has emerged as a key regulator of several aspects of mammalian energy metabolism including mitochondrial biogenesis, adaptive thermogenesis in brown adipose tissue, glucose uptake, fiber type-switching in skeletal muscle, gluconeogenesis in liver and insulin secretion from pancreas. Recent studies have shown a reduced expression of PGC-1alpha in skeletal muscle of diabetic and prediabetic humans. Moreover, expression of PGC-1alpha in white fat cells activates a broad program of adaptive thermogenesis characteristic of brown fat cells. PGC-1alpha could be a target for antiobesity or diabetes drugs. The aim of this article was to summarize the molecular mechanisms and biological programs controlled by the transcriptional coactivator PGC-1alpha.