Showing papers by "Bruce M. Spiegelman published in 2003"
TL;DR: An analytical strategy is introduced, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes, which identifies a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle.
Abstract: DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1α and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.
7,997 citations
TL;DR: PGC-1 alpha constitutes one of the first and clearest examples in which biological programs are chiefly regulated by a transcriptional coactivator in response to environmental stimuli and its control of energy homeostasis suggests that it could be a target for anti-obesity or diabetes drugs.
Abstract: Investigations of biological programs that are controlled by gene transcription have mainly studied the regulation of transcription factors. However, there are examples in which the primary focus of biological regulation is at the level of a transcriptional coactivator. We have reviewed here the molecular mechanisms and biological programs controlled by the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha). Key cellular signals that control energy and nutrient homeostasis, such as cAMP and cytokine pathways, strongly activate PGC-1 alpha. Once PGC-1 alpha is activated, it powerfully induces and coordinates gene expression that stimulates mitochondrial oxidative metabolism in brown fat, fiber-type switching in skeletal muscle, and multiple aspects of the fasted response in liver. The regulation of these metabolic and cell fate decisions by PGC-1 alpha is achieved through specific interaction with a variety of transcription factors such as nuclear hormone receptors, nuclear respiratory factors, and muscle-specific transcription factors. PGC-1 alpha therefore constitutes one of the first and clearest examples in which biological programs are chiefly regulated by a transcriptional coactivator in response to environmental stimuli. Finally, PGC-1 alpha's control of energy homeostasis suggests that it could be a target for anti-obesity or diabetes drugs.
1,990 citations
TL;DR: It is concluded that FOXO1 and PGC-1α interact in the execution of a programme of powerful, insulin-regulated gluconeogenesis, which is necessary for survival during prolonged fasting or starvation and in diabetes mellitus.
Abstract: Hepatic gluconeogenesis is absolutely required for survival during prolonged fasting or starvation, but is inappropriately activated in diabetes mellitus. Glucocorticoids and glucagon have strong gluconeogenic actions on the liver. In contrast, insulin suppresses hepatic gluconeogenesis. Two components known to have important physiological roles in this process are the forkhead transcription factor FOXO1 (also known as FKHR) and peroxisome proliferative activated receptor-gamma co-activator 1 (PGC-1alpha; also known as PPARGC1), a transcriptional co-activator; whether and how these factors collaborate has not been clear. Using wild-type and mutant alleles of FOXO1, here we show that PGC-1alpha binds and co-activates FOXO1 in a manner inhibited by Akt-mediated phosphorylation. Furthermore, FOXO1 function is required for the robust activation of gluconeogenic gene expression in hepatic cells and in mouse liver by PGC-1alpha. Insulin suppresses gluconeogenesis stimulated by PGC-1alpha but co-expression of a mutant allele of FOXO1 insensitive to insulin completely reverses this suppression in hepatocytes or transgenic mice. We conclude that FOXO1 and PGC-1alpha interact in the execution of a programme of powerful, insulin-regulated gluconeogenesis.
1,346 citations
TL;DR: It is shown that the PGC-1α promoter is regulated by both CaMKIV and CnA activity, implying a unified pathway, integrating key regulators of calcium signaling with the transcriptional switch P GC-1 α, contributing to the relatively stable nature of muscle fiber-type determination.
Abstract: Skeletal muscle adapts to chronic physical activity by inducing mitochondrial biogenesis and switching proportions of muscle fibers from type II to type I. Several major factors involved in this process have been identified, such as the calcium/calmodulin-dependent protein kinase IV (CaMKIV), calcineurin A (CnA), and the transcriptional component peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Transgenic expression of PGC-1α recently has been shown to dramatically increase the content of type I muscle fibers in skeletal muscle, but the relationship between PGC-1α expression and the key components in calcium signaling is not clear. In this report, we show that the PGC-1α promoter is regulated by both CaMKIV and CnA activity. CaMKIV activates PGC-1α largely through the binding of cAMP response element-binding protein to the PGC-1α promoter. Moreover, we show that a positive feedback loop exists between PGC-1α and members of the myocyte enhancer factor 2 (MEF2) family of transcription factors. MEF2s bind to the PGC-1α promoter and activate it, predominantly when coactivated by PGC-1α. MEF2 activity is stimulated further by CnA signaling. These findings imply a unified pathway, integrating key regulators of calcium signaling with the transcriptional switch PGC-1α. Furthermore, these data suggest an autofeedback loop whereby the calcium-signaling pathway may result in a stable induction of PGC-1α, contributing to the relatively stable nature of muscle fiber-type determination.
663 citations
TL;DR: It is shown here that PGC-1α completely loses its ability to activate key genes of gluconeogenesis such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase when HNF4α is absent.
Abstract: The liver plays several critical roles in the metabolic adaptation to fasting. We have shown previously that the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is induced in fasted or diabetic liver and activates the entire program of gluconeogenesis. PGC-1α interacts with several nuclear receptors known to bind gluconeogenic promoters including the glucocorticoid receptor, hepatocyte nuclear factor 4α (HNF4α), and the peroxisome proliferator-activated receptors. However, the genetic requirement for any of these interactions has not been determined. Using hepatocytes from mice lacking HNF4α in the liver, we show here that PGC-1α completely loses its ability to activate key genes of gluconeogenesis such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase when HNF4α is absent. It is also shown that PGC-1α can induce genes of β-oxidation and ketogenesis in hepatocytes, but these effects do not require HNF4α. Analysis of the glucose-6-phosphatase promoter indicates a key role for HNF4α-binding sites that function robustly only when HNF4α is coactivated by PGC-1α. These data illustrate the involvement of PGC-1α in several aspects of the hepatic fasting response and show that HNF4α is a critical component of PGC-1α-mediated gluconeogenesis.
546 citations
TL;DR: Detailed bioenergetic analyses of the function of P GC-1α and its homolog PGC-1β in muscle cells by monitoring simultaneously oxygen consumption and membrane potential suggest that these proteins are likely to play different physiological functions.
516 citations
TL;DR: Muscle PPARgamma is not required for the antidiabetic effects of TZDs, but has a hitherto unsuspected role for maintenance of normal adiposity, whole-body insulin sensitivity, and hepatic insulin action.
Abstract: Activation of peroxisome proliferator-activated receptor γ (PPARγ) by thiazolidinediones (TZDs) improves insulin resistance by increasing insulin-stimulated glucose disposal in skeletal muscle. It remains debatable whether the effect of TZDs on muscle is direct or indirect via adipose tissue. We therefore generated mice with muscle-specific PPARγ knockout (MuPPARγKO) using Cre/loxP recombination. Interestingly, MuPPARγKO mice developed excess adiposity despite reduced dietary intake. Although insulin-stimulated glucose uptake in muscle was not impaired, MuPPARγKO mice had whole-body insulin resistance with a 36% reduction (P < 0.05) in the glucose infusion rate required to maintain euglycemia during hyperinsulinemic clamp, primarily due to dramatic impairment in hepatic insulin action. When placed on a high-fat diet, MuPPARγKO mice developed hyperinsulinemia and impaired glucose homeostasis identical to controls. Simultaneous treatment with TZD ameliorated these high fat–induced defects in MuPPARγKO mice to a degree identical to controls. There was also altered expression of several lipid metabolism genes in the muscle of MuPPARγKO mice. Thus, muscle PPARγ is not required for the antidiabetic effects of TZDs, but has a hitherto unsuspected role for maintenance of normal adiposity, whole-body insulin sensitivity, and hepatic insulin action. The tissue crosstalk mediating these effects is perhaps due to altered lipid metabolism in muscle.
417 citations
TL;DR: Results suggest a key role for PGC-1alpha, through concerted but dynamic interactions, in coordinating these steps in chromatin remodeling and in preinitiation complex formation or function (transcription).
244 citations
TL;DR: The reduced ability of PGC-1β to induce gluconeogenic genes is due, at least in part, to its inability to physically associate with and coactivate hepatic nuclear receptor 4α (HNF4α) and forkhead transcription factor O1 (FOXO1), two critical transcription factors that mediate the activation of gluc oneogenic gene expression by P GC-1α.
231 citations
TL;DR: While clinical trials among different patient populations might uncover subtle effects on tumor differentiation, PPARγ activation by troglitazone has little apparent clinical value among patients with treatment-refractory metastatic breast cancer.
Abstract: Purpose. To evaluate the therapeutic effects of the peroxisome proliferator-activated receptor (PPAR) γ activating ligand, troglitazone, in patients with refractory metastatic breast cancer.
231 citations
TL;DR: It is shown that activation of PPARγ is sufficient to reduce the proliferation of cultured insulinoma cell lines and indicates that the mechanisms controlling β-cell hyperplasia in obesity are different from those that regulate baseline cell mass in the islet.
Abstract: The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) is an important regulator of lipid and glucose homeostasis and cellular differentiation. Studies of many cell types in vitro and in vivo have demonstrated that activation of PPAR gamma can reduce cellular proliferation. We show here that activation of PPAR gamma is sufficient to reduce the proliferation of cultured insulinoma cell lines. We created a model with mice in which the expression of the PPARG gene in beta cells was eliminated (beta gamma KO mice), and these mice were found to have significant islet hyperplasia on a chow diet. Interestingly, the normal expansion of beta-cell mass that occurs in control mice in response to high-fat feeding is markedly blunted in these animals. Despite this alteration in beta-cell mass, no effect on glucose homeostasis in beta gamma KO mice was noted. Additionally, while thiazolidinediones enhanced insulin secretion from cultured wild-type islets, administration of rosiglitazone to insulin-resistant control and beta gamma KO mice revealed that PPAR gamma in beta cells is not required for the antidiabetic actions of these compounds. These data demonstrate a critical physiological role for PPAR gamma function in beta-cell proliferation and also indicate that the mechanisms controlling beta-cell hyperplasia in obesity are different from those that regulate baseline cell mass in the islet.
TL;DR: It is suggested that PGC-1alpha plays a key functional role in the beta cell and is involved in the pathogenesis of the diabetic phenotype.
TL;DR: PGC-1alpha is widely expressed in the rodent brain, but is not regulated by states of caloric deficiency, leptin, obesity or cold exposure, and its functional role in the brain requires further study.
Patent•
13 Feb 2003TL;DR: In this paper, the authors provide novel methods and compositions for modulating type I muscle formation through modulation of PGC-1α activity or expression, as well as methods for identifying compounds that modulate type I and/or type II muscle formation.
Abstract: The invention provides novel methods and compositions for modulating type I muscle formation through modulation of PGC-1α activity or expression. Also provided are methods for identifying compounds that modulate type I muscle formation through modulation of PGC-1α activity or expression. Further provided are methods for treating disorders associated with type I and/or type II muscle formation, as well as transgenic animals expressing PGC-1α in muscle.