Metabolic pathways are controlled at different levels in response to environmental or hormonal stimuli. This control is achieved, at least in part, at the transcriptional level of gene expression. The regulation of gene expression is executed by specific transcription factors, but there is another level of regulation by a set of proteins that modulate these factors called transcriptional coactivators. In mammals, one of the most characterized examples of regulation of metabolic pathways by transcriptional coactivators is peroxisome proliferator-activated receptors gamma (PPARγ) coactivator-1 alpha (PGC-1α). PGC-1α is activated by signals that control energy and nutrient homeostasis. Notably, PGC-1α induces and coordinates gene expression that stimulates mitochondrial biogenesis and a thermogenic program in brown fat, fiber-type switching in skeletal muscle, and metabolic pathways linked to the fasted response in the liver. PGC-1α activates gene expression through specific interaction with transcription factors that bind to the promoters of metabolic genes. These transcription factors can be ubiquitous such as the nuclear respiratory factors or tissue-enriched factors such as PPARγ (brown fat), hepatocyte nuclear factor (HNF4α) (liver and pancreas) and muscle enhancer factor (MEF2s). The fact that PGC-1α controls important metabolic pathways in several tissues suggests that it can be a therapeutic target for antiobesity or diabetes drugs.
Molecular mechanisms of PGC-1α (PPAR gamma coactivator-1α) function
Gene transcription is a highly regulated nuclear process orchestrated by multiprotein complexes with many enzymatic activities and takes place in sequential and dynamic steps. There are recent reviews describing in detail how gene transcription is initiated and the multiprotein complexes that execute gene expression.1 From a regulatory point of view, the key question in this process is which factors linked to signaling pathways turn the transcriptional machinery on/off. There are many examples in which the regulated target protein is a transcription factor. However, in the last 5 y, we have demonstrated that in different biological programs, gene regulation is achieved by a transcriptional coactivator named PGC-1α, which in contrast to transcription factors lacks a DNA-binding domain.2, 3 Indeed, PGC-1α acts as a sensor for different signaling pathways that regulate its expression, phosphorylation, stability and transcriptional activity – see next sections. Once PGC-1α is activated, it is recruited to the chromatin through interaction with transcription factors. After docking to a transcription factor, PGC-1α undergoes a conformational change that allows interaction with histone acetyl transferases (HAT) such as p300 and steroid receptor coactivator (SRC-1). This set of proteins interacts at the PGC-1α N-terminal region that contains a potent transcriptional activation domain.4 Interestingly, this interaction of PGC-1α and HAT proteins is not sufficient to activate gene transcription. The docking of the thyroid receptor (TR)-associated protein (TRAP) complex through the protein TRAP220 at the C-terminal domain of the PGC-1α is required to complete transcription.5 These data reveal that the regulation of gene expression by PGC-1α is achieved by a sequential and dynamic recruitment of different set of proteins making a functional multiprotein complex that transcribes specific genes.
Adipocyte cell fate and thermogenesis
In mammals, chronic variations in energy balance can lead to an increase or decrease of body weight. Two components are defined in energy balance: energy intake and energy expenditure. Perturbations in energy intake and/or energy expenditure can cause obesity, a metabolic disease characterized by an excess of white adipose tissue, and a predisposition toward the development of cardiovascular diseases and type 2 diabetes. White adipose tissue stores energy in the form of triacylglycerols that are used as an energy source in situations such as fasting. Brown adipose tissue is a highly thermogenic tissue that dissipates energy as heat. In small mammals, most of the adaptive energy expenditure is produced in brown adipose tissue. At the gene expression level, the main difference between brown and white adipose tissues is the high level of expression of mitochondrial genes (encoded by the nucleus and mitochondria) in the brown adipose tissue.6 One of the key mitochondrial genes is the brown fat-specific uncoupling protein UCP-1, a highly expressed protein that uncouples the mitochondrial proton gradient and ATP synthesis. Although the thermogenic contribution of brown adipose tissue in adult large mammals is relatively low, muscle being the primary thermogenic tissue, it is important to note that brown fat depots can be induced under pharmacological or pathological conditions.
UCP-1 levels are mainly controlled at the transcriptional level. UCP-1 gene expression is highly induced by cold through the activation of the sympathetic nervous system via β-adrenoreceptors and cAMP signaling. Importantly, several nuclear hormone receptors, such as retinoic acid receptor, TR, peroxisome proliferator-activated receptors PPARα and PPARγ, have been shown to be positive regulators of UCP-1 through binding to its enhancer. PPARγ, a master regulator of adipocyte differentiation, is required for brown fat formation and PPARγ ligands potently induce brown fat differentiation and UCP-1 gene expression.7 However, PPARγ activation is not sufficient to induce brown adipocyte differentiation, and in fibroblast cell lines, ectopic expression of PPARγ will always lead to white adipocyte differentiation. Based on this PPARγ requirement but not sufficient to induce thermogenic brown adipocytes, we hypothesized the existence of a putative cofactor for PPARγ to be expressed in brown but not white adipocytes. As a result we identified a cofactor called PGC-1α.8
The key set of experiments to provide evidence that PGC-1α was sufficient to induce brown adipocyte differentiation were first established using white fat cell lines in which ectopic expression of PGC-1α induced mitochondrial biogenesis as well as UCP-1.8 Recently, similar conceptual experiments have been addressed in human subcutaneous white adipocytes and in mouse white fat pads in vivo. Again, a full induction of brown adipocyte markers linked to energy dissipation including UCP-1, respiratory chain proteins and fatty acid oxidation enzymes were observed.9 Importantly, activation of PGC-1α can convert white adipocytes into brown fat cells converting a cell that functions to store energy into a thermogenic cell that dissipates energy. However, the requirement of PGC-1α for brown adipocyte differentiation has not yet been proven.
As discussed in the previous section, PGC-1α activates gene expression via interaction with transcription factors. In brown fat, several transcription factors are used by PGC-1α to coordinate the thermogenic response. For UCP-1 gene expression, PGC-1α interacts with different nuclear hormone receptors depending on the stimuli, PPARγ being one of the key transcription factors. The induction of mitochondrial genes linked to respiration is partially dependent on the ubiquitous nuclear respiratory factors NRF-1 and NRF-2, although a contribution by the thyroid hormone receptor is likely when triiodothyronine levels are increased. On the activation of fatty acid oxidation enzymes such as medium chain acyl-CoA dehydrogenase and carnitine palmitoyl transferase, PGC-1α uses different transcription factors that are highly expressed in brown adipocytes such as PPARα and estrogen-related receptor α.10 Therefore, PGC-1α establishes and coordinates a transcriptional regulatory network by using specific and ubiquitous transcription factors to induce gene expression that is linked to energy dissipation.
Activation and recruitment of brown adipose tissue occur to meet thermogenic requirements in mammals. One of the important environmental stimuli is cold adaptation that activates sympathetic nervous input and activation of G proteins linked to the β-adrenoreceptors. Increases of cAMP activate protein kinase (PKA) that phosphorylates cAMP response element binding protein (CREB) transcription factor, an important regulator of PGC-1α gene expression. In addition, in brown fat cells, cAMP activates p38 mitogen-activated protein (MAP) kinase that directly phosphorylates and stabilizes PGC-1α protein.11, 12 Once PGC-1α is fully active, it triggers gene expression associated with the thermogenic response.
Obesity is a metabolic disorder where energy intake exceeds energy expenditure. This leads to a massive accumulation of white adipose tissue. So far, experimental evidence supports the notion that therapeutic strategies to convert white adipocytes into more oxidative ‘brown’ adipocytes could contribute to a decrease in fat mass and body weight. The fact that PGC-1α is sufficient to induce a highly oxidative state in adipocytes suggests that it could be a therapeutic target for antiobesity drugs.
Muscle and fiber-type switching
PGC-1α function in skeletal muscle constitutes another clear example in which a transcriptional coactivator can modulate cell fate and metabolic decisions. An important component of energy balance is physical activity that contributes to energy dissipation. In this regard, skeletal muscle is the main tissue that contributes to energy expenditure during exercise. The adaptation to physical activity includes mitochondrial biogenesis and a conversion of muscle fibers from type II (fast twitch) to type I (slow twitch). Type I fibers are characterized by an increased mitochondrial number and oxidative state as well as a specific set of contractile proteins such as troponin I slow and myoglobin. PGC-1α was originally shown to induce mitochondrial biogenesis in skeletal muscle cell lines.13 In addition, specific mouse transgenic expression of PGC-1α in muscle results in a massive increase of type 1 fibers and a resistance to muscle fatigue.14 PGC-1α is orchestrating this muscle-specific biological program using the same strategy as in fat cells but ‘sensing’ different signaling pathways and interacting with muscle-selective and ubiquitous transcription factors.
Several key proteins have been identified in the signaling cascades that control and induce a fiber switching program during adaptation to exercise. Motor nerve activity induces an intracellular increase of calcium that activates CaMKIV (calcium/calmodulin-dependent protein kinase) and calcineurin (CaN). CaMKIV phosphorylates and induces a cytoplasmic translocation of muscle enhancer factor (MEF2C) corepressors including HDAC1/2 and 4/5. As a consequence, MEF2C interacts with other transcriptional coactivators such as p300 or PGC-1α that is induced by CaMKIV. In addition, calcium activates the protein phosphatase CaN that dephosphorylates nuclear factor of activated T cells (NFAT) transcription factors. The transcriptional activation of MEF2s and NFAT results in a conversion from type II to type I fibers. Importantly, transgenic animal data reveal that activation of PGC-1α is sufficient for this muscle fiber switch. PGC-1α is preferentially expressed in type I fibers and is induced by chronic physical activity. This increase of PGC-1α is achieved mainly through the calcium signaling.15 CaMKIV induces PGC-1α promoter through CREB and MEF2s binding sites. CaN signaling through MEF2s also activates PGC-1α expression. Therefore, an autoregulatory loop is established by MEF2s/PGC-1α maintaining a type I fiber phenotype.16 As in brown fat cells, mitochondrial biogenesis in skeletal muscle depends upon the NRF1/NRF2 system. In summary, PGC-1α induces specific type I fiber gene expression via interaction with skeletal muscle-selective transcription factors such as MEF2s and ubiquitous regulators such as the NRFs.
Although PGC-1α function in skeletal fiber-type cell fate is well established and a great detail of molecular mechanisms are known, metabolic consequences of this highly oxidative muscle mass in PGC-1α transgenic animals are poorly understood. It is known that type I fibers are more insulin sensitive, but how insulin signaling is affecting PGC-1α function in skeletal muscle is unknown. Interestingly, a decrease in mitochondrial mass and PGC-1α has been found in type II diabetic patients associated with a decrease in oxygen consumption.17 Certainly, an increase in muscle nutrient oxidation through activation of PGC-1α or other protein in the same pathway could be therapeutically valuable for antiobesity or diabetic drugs.
Liver and the fasting response
It is clear that an important regulator of PGC-1α gene expression is the cAMP pathway and activation of CREB transcription factor. Therefore, a possible strategy to evaluate the biological function of PGC-1α in a given specific tissue is when intracellular levels of cAMP are elevated. One of these physiological examples is the fasting state in the liver. The liver is a major metabolic tissue responsible for nutrient homeostasis in mammals. Among nutrients, blood glucose levels are tightly controlled, despite intermittent ingestion of food. One of the reasons is that central nervous system and red blood cells depend on this substrate as an energy source. Importantly, blood glucose levels are mainly controlled by hormones such as glucagon and insulin. The blood glucose sensor is localized in the pancreas where glucose fluctuations are sensed by insulin producing β-cells. In addition, blood glucose levels depend on glucose uptake and glucose production. The arm of glucose production takes place mainly in the liver and is regulated positively by glucagon and negatively by insulin. In feeding/fasting conditions, these counter-regulatory hormones will maintain blood glucose levels. Alterations in the production and/or sensitivity of these hormones will affect glucose production in the liver. This is particularly important in either type 1 or type 2 diabetes where the gluconeogenic pathway is constantly activated.
Gluconeogenesis or de novo synthesis of glucose occurs from precursors such as alanine, lactate and glycerol. It is a highly polarized metabolic pathway involving biochemical reactions in different compartments such as the cytoplasm, mitochondria, endoplasmic reticulum and plasma membrane. The rate of gluconeogenesis is controlled by three key enzymes: phosphoenol-pyruvate carboxykinase (PEPCK), fructose 1,6-bisphosphatase and glucose-6-phosphatase (G-6-Pase). Hormonal control of these enzymes is achieved at the transcriptional level. The main positive signals to turn on gluconeogenesis are activated during fasting, stress and diabetes. Among these signals are glucagon that produces an increase in intracellular cAMP and glucocorticoids, endogenous ligands for the glucocorticoid receptor (GR). After food intake, insulin is the main negative signal to turn off gluconeogenesis. As a consequence of this strict hormonal regulation, control of the gene expression of the key gluconeogenic enzymes is very precise. Important work by Hanson and Granner's groups has elucidated most of the transcription factors controlling gluconeogenic genes, but to what extent these transcription factors were tightly regulated by hormonal control was not totally understood. The fact that PGC-1α was a downstream target of the cAMP cascade and also was induced in fasting and mouse models of either type 1 or type 2 diabetes suggested a potential role for this coactivator in the gluconeogenic pathway. In addition, both PEPCK and G-6-Pase contain key binding sites for hormone nuclear receptors such as hepatocyte nuclear factor (HNF4α). Remarkably, we and others have shown that PGC-1α is an important regulator of the gluconeogenic metabolic pathway and we have dissected how cAMP and insulin can regulate expression of the gluconeogenic enzymes.18, 19 Positive signals such as glucagon activate, via cAMP, the CREB transcription factor, an important regulator of PGC-1α gene expression. In addition, glucocorticoids strongly synergize with cAMP to induce PGC-1α levels. Once PGC-1α is activated, it binds and coactivates different transcription factors such as HNF4α, forkhead box O1a (FOXO1) and GR to coordinate expression of gluconeogenic genes. Genetic and cellular experiments have provided evidence for requirement of HNF4α and FOXO1 in the PGC-1α-mediated induction of these genes.20, 21 Insulin, a dominant-negative signal, powerfully decreases the transcription rate of gluconeogenic enzymes. In this case, FOXO1 acts as a cellular sensor of insulin signaling via Akt. Akt phosphorylates FOXO1 and induces cytoplasmic localization and degradation. PGC-1α requires FOXO1 to bind and localize to the promoter chromatin region of gluconeogenic genes. So far, HNF4α and FOXO1 are key transcription factors required for PGC-1α induction of gluconeogenic genes; however, PGC-1α also activates other metabolic pathways in the fasted liver such as fatty acid oxidation and ketogenesis. Several key enzymes in these pathways are also induced via PGC-1α, but HNF4α and FOXO1 are not required.
Again, and similar to brown adipocytes and skeletal muscle, PGC-1α in hepatocytes controls tissue-specific gene expression via interaction with liver-enriched transcription factors such as HNF4α and more ubiquitous transcription factors such as GR, FOXO1 and PPARα among others. PGC-1α controls the fasted metabolic response in hepatocytes that is similar to the diabetic state, especially in the case of uncontrolled glucose production. The fact that these specific, by either tissue or signaling cascades, interactions between transcription factors and PGC-1α control glucose production that is highly elevated in diabetes opens the possibility to screen for small molecules to target specific docking events and modulate gene expression.
In mammals, energy metabolism must be tightly controlled to provide enough nutrients to the different tissues to perform their specific function and to ensure survival. Failure to keep this control provokes high incidence of metabolic diseases such as obesity and diabetes. In this short review, it is emphasized how important metabolic decisions and functions are controlled by PGC-1α in a tissue-specific manner in brown fat, muscle and liver. Although it would seem that this transcriptional coactivator regulates large and nonrelated metabolic pathways, a common ground for PGC-1α function is its control over oxidative metabolism. Importantly, the fact that PGC-1α is a key metabolic ‘controller’ opens a great possibility of being a target for antiobesity and diabetes drugs. In this case, the challenge would be to find small molecules to target tissue-specific protein–protein interactions between PGC-1α and transcription factors. Furthermore, a lot remains to be uncovered about PGC-1α (and other members of the PGC-1 family) function and regulation in different tissues where it is highly expressed such as the brain and kidney. Certainly, upcoming studies of mouse genetics, in combination with other basic experimental approaches, will provide us with new information about PGC-1's role in energy metabolism.
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I thank Dr Bruce Spiegelman and his laboratory for his support and helpful discussions over the last years. I also thank Francisca Vazquez and members of the Puigserver's laboratory, Joseph Rodgers and Tom Cunningham for careful reading of this review.
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Puigserver, P. Tissue-specific regulation of metabolic pathways through the transcriptional coactivator PGC1-α. Int J Obes 29, S5–S9 (2005). https://doi.org/10.1038/sj.ijo.0802905
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