Transcriptional coactivators PGC-1alpha and PGC-lbeta control overlapping programs required for perinatal maturation of the heart. Genes Dev

Center for Cardiovascular Research, Washington University School of Medicine, St Louis, Missouri 63110, USA
Genes & Development (Impact Factor: 12.64). 07/2008; 22(14):1948-61. DOI: 10.1101/gad.1661708
Source: PubMed

ABSTRACT Oxidative tissues such as heart undergo a dramatic perinatal mitochondrial biogenesis to meet the high-energy demands after birth. PPARgamma coactivator-1 (PGC-1) alpha and beta have been implicated in the transcriptional control of cellular energy metabolism. Mice with combined deficiency of PGC-1alpha and PGC-1beta (PGC-1alphabeta(-/-) mice) were generated to investigate the convergence of their functions in vivo. The phenotype of PGC-1beta(-/-) mice was minimal under nonstressed conditions, including normal heart function, similar to that of PGC-1alpha(-/-) mice generated previously. In striking contrast to the singly deficient PGC-1 lines, PGC-1alphabeta(-/-) mice died shortly after birth with small hearts, bradycardia, intermittent heart block, and a markedly reduced cardiac output. Cardiac-specific ablation of the PGC-1beta gene on a PGC-1alpha-deficient background phenocopied the generalized PGC-1alphabeta(-/-) mice. The hearts of the PGC-1alphabeta(-/-) mice exhibited signatures of a maturational defect including reduced growth, a late fetal arrest in mitochondrial biogenesis, and persistence of a fetal pattern of gene expression. Brown adipose tissue (BAT) of PGC-1alphabeta(-/-) mice also exhibited a severe abnormality in function and mitochondrial density. We conclude that PGC-1alpha and PGC-1beta share roles that collectively are necessary for the postnatal metabolic and functional maturation of heart and BAT.

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    • "We therefore examined whether postnatal changes in HIF signaling and/or ambient oxygen levels lead to altered expression of Pgc1α/β. We found a postnatal increase in Pgc1α mRNA expression following birth in control hearts, as previously reported [5]; we found no significant difference in Pgc1α mRNA expression between P2.5 αMHC-Cre::VHL (fl/fl) and control hearts (Fig. 5D). However , we observed a significant decrease in Pgc1α RNA expression in cardiac ventricles from mice born in 10% ambient oxygen compared with normoxic controls (p = 0.019, 2 tailed t-test, 4 hearts each group). "
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    ABSTRACT: Fetal cardiomyocyte adaptation to low levels of oxygen in utero is incompletely understood, and is of interest as hypoxia tolerance is lost after birth, leading to vulnerability of adult cardiomyocytes. It is known that cardiac mitochondrial morphology, number and function change significantly following birth, although the underlying molecular mechanisms and physiological stimuli are undefined. Here we show that the decrease in cardiomyocyte HIF-signaling in cardiomyocytes immediately after birth acts as a physiological switch driving mitochondrial fusion and increased postnatal mitochondrial biogenesis. We also investigated mechanisms of ATP generation in embryonic cardiac mitochondria. We found that embryonic cardiac cardiomyocytes rely on both glycolysis and the tricarboxylic acid cycle to generate ATP, and that the balance between these two metabolic pathways in the heart is controlled around birth by the reduction in HIF signaling. We therefore propose that the increase in ambient oxygen encountered by the neonate at birth acts as a key physiological stimulus to cardiac mitochondrial adaptation.
    Journal of Molecular and Cellular Cardiology 06/2014; 74. DOI:10.1016/j.yjmcc.2014.06.013 · 5.22 Impact Factor
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    • "Accordingly, PGC-1b function has been studied mostly in tissues like BAT, skeletal muscle or heart, where it regulates mitochondrial gene expression and cell respiration [21] [22] [23] [24]. In at least some of these tissues, PGC-1α and PGC-1b coactivators seem to carry redundant roles in the control of mitochondrial oxidative capacity [24] [25]. In addition, both PGC-1α and PGC-1b carry distinct and nonredundant roles in the regulation of glucose and lipid metabolism in liver, with PGC-1α controlling hepatic gluconeogenesis in response to fasting [26] and PGC-1b regulating triglyceride synthesis and VLDL secretion [27] [28]. "
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    ABSTRACT: Proper development and function of white adipose tissue (WAT), which are regulated by multiple transcription factors and coregulators, are crucial for glucose homeostasis. WAT is also the main target of thiazolidinediones, which are thought to exert their insulin-sensitizing effects by promoting mitochondrial biogenesis in adipocytes. Besides being expressed in WAT, the role of the coactivator PGC-1β in this tissue has not been addressed. To study its function in WAT, we have generated mice that lack PGC-1β in adipose tissues. Gene expression profiling analysis of WAT reveals that PGC-1β regulates mitochondrial genes involved in oxidative metabolism. Furthermore, lack of PGC-1β prevents the induction of mitochondrial genes by rosiglitazone in WAT without affecting the capacity of thiazolidinediones to enhance insulin sensitivity. Our findings indicate that PGC-1β is important for basal and rosiglitazone-induced mitochondrial function in WAT, and that induction of mitochondrial oxidative capacity is not essential for the insulin-sensitizing effects of thiazolidinediones.
    08/2013; 2(3):215-26. DOI:10.1016/j.molmet.2013.05.004
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    • "For ChIP and co-immunoprecipitation studies, hepatocytes were dispersed and crosslinked or cells were plated. Hepatocytes were infected with previously described adenovirus constructs to overexpress PGC-1β [3] or GFP at time of plating, and endpoints were harvested 48 h post-infection. "
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    ABSTRACT: Peroxisome proliferator-activated receptorγ coactivators (PGC-1α and PGC-1β) play important roles in the transcriptional regulation of intermediary metabolism. To evaluate the effects of overexpressing PGC-1α or PGC-1β at physiologic levels in liver, we generated transgenic mice with inducible overexpression of PGC-1α or PGC-1β. Gene expression array profiling revealed that whereas both PGC-1 family proteins induced mitochondrial oxidative enzymes, the expression of several genes involved in converting glucose to fatty acid was induced by PGC-1β, but not PGC-1α. The increased expression of enzymes involved in carbohydrate utilization and de novo lipogenesis by PGC-1β required carbohydrate response element binding protein (ChREBP). The interaction between PGC-1β and ChREBP, as well as PGC-1β occupancy of the liver-type pyruvate kinase promoter, was influenced by glucose concentration and liver-specific PGC-1β(-/-) hepatocytes were refractory to the lipogenic response to high glucose conditions. These data suggest that PGC-1β-mediated coactivation of ChREBP is involved in the lipogenic response to hyperglycemia.
    08/2013; 2(3):194-204. DOI:10.1016/j.molmet.2013.05.001
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