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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have explored the effects of two members of the p160 coregulator family on energy homeostasis. TIF2-/- mice are protected against obesity and display enhanced adaptive thermogenesis, whereas SRC-1-/- mice are prone to obesity due to reduced energy expenditure. In white adipose tissue, lack of TIF2 decreases PPARgamma activity and reduces fat accumulation, whereas in brown adipose tissue it facilitates the interaction between SRC-1 and PGC-1alpha, which induces PGC-1alpha's thermogenic activity. Interestingly, a high-fat diet increases the TIF2/SRC-1 expression ratio, which may contribute to weight gain. These results reveal that the relative level of TIF2/SRC-1 can modulate energy metabolism.
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PMID:SRC-1 and TIF2 control energy balance between white and brown adipose tissues. 1250 21

The peroxisome proliferator activated receptor coactivator 1 alpha (PGC-1alpha) is a nuclear transcriptional coactivator that is expressed in brown adipose tissue, brain, heart and kidney as well as cold-exposed skeletal muscle. In liver, white and brown adipose tissue, PGC-1alpha expression is regulated in a manner suggesting a role in energy homeostasis. To characterize PGC-1alpha expression in the rodent brain and to determine brain PGC-1alpha regulation, we used in situ hybridization histochemistry in C57Bl/6J mice and Sprague-Dawley rats. We found that PGC-1alpha is widely expressed in brain areas, including in the olfactory bulb, cerebral cortex, the diagonal band of Broca, the medial septal nucleus, reticular thalamic nucleus, the striatum and globus pallidus, the hippocampus, the substantia nigra, the mesencephalic nucleus of the trigeminal nerve, the cochlear nucleus and the superior olivary complex. In contrast, PGC-1alpha expression was absent in the hypothalamus. To evaluate PGC-1alpha expression under different physiologic states in these various brain areas, we examined expression with fasting, leptin treatment and cold exposure (4 h at 4 degrees C) and found no change, nor was expression changed in the brain of the leptin-deficient ob/ob mice and the hyperleptinemic UCP-DTA mice. Hence, PGC-1alpha is widely expressed in the rodent brain, but is not regulated by states of caloric deficiency, leptin, obesity or cold exposure. Its functional role in the brain requires further study.
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PMID:Characterization of the peroxisome proliferator activated receptor coactivator 1 alpha (PGC 1alpha) expression in the murine brain. 1253 92

A well balanced body energy budget controlled by limitation of calorie uptake and/or increment of energy expenditure, which is typically achieved by proper physical exercise, is most effective against obesity and diabetes mellitus. Recently, peroxisome proliferator-activated receptor (PPAR) gamma, a member of the nuclear receptor, and its cofactors have been shown to be involved in lipid metabolism and in the control of energy expenditure. Here we show that PPARgamma coactivator 1 (PGC-1) beta functions as ERRL1 (for ERR ligand 1), which can bind and activate orphan ERRs (estrogen receptor-related receptors) in vitro. Consistently, PGC-1beta/ERRL1 transgenic mice exhibit increased expression of the medium-chain acyl CoA dehydrogenase, a known ERR target and a pivotal enzyme of mitochondrial beta-oxidation in skeletal muscle. As a result, the PGC-1beta/ERRL1 mice show a state similar to an athlete; namely, the mice are hyperphagic and of elevated energy expenditure and are resistant to obesity induced by a high-fat diet or by a genetic abnormality. These results demonstrate that PGC-1beta/ERRL1 can function as a protein ligand of ERR, and that its level contributes to the control of energy balance in vivo, and provide a strategy for developing novel antiobesity drugs.
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PMID:PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. 1453 Mar 91

Mitochondrial content, a chief determinant of aerobic capacity, varies widely among muscle types and species. Mitochondrial enzyme levels in vertebrate skeletal muscles vary more than 100-fold, from fish white muscle to bird flight muscles. Recent studies have shed light on the transcriptional regulators that control mitochondrial gene expression in muscle fiber differentiation and development, and in the context of pathological conditions such as neuromuscular disease and obesity. While the transcriptional co-activator PGC-1alpha (peroxisome proliferator-activated receptor gamma co-activator 1) has emerged as a master controller of mitochondrial gene expression, it is important to consider other mechanisms by which coordinated changes in mitochondrial content could arise. These studies, largely using biomedical models, provide important information for comparative biologists interested in the mechanistic basis of inter-species variation in muscle aerobic capacity.
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PMID:Controlling muscle mitochondrial content. 1461 25

Understanding the mechanisms governing the acquisition of white and brown adipocyte phenotypes might have implications for the physiopathology of, and therapeutic strategies for obesity. Peroxisome proliferator-activated recetor gamma (PPARgamma) and its coactivators, PGC-1alpha and SRC-1, influence brown adipocyte metabolism and development. Ectopic expression of PGC-1alpha induces the expression of brown adipocyte genes in human white adipocytes. The changes in gene expression promote stimulation of fatty acid oxidation. There is now evidence to support the concept of an alteration in energy balance through a conversion of white to brown adipose tissue.
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PMID:Conversion from white to brown adipocytes: a strategy for the control of fat mass? 1464 55

Peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha) is a transcriptional coactivator that is a key component in the regulation of energy production and utilization in metabolic tissues. Recent work has identified PGC-1alpha as a strong coactivator of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha), implicating ERRalpha as a potential mediator of PGC-1alpha action. To understand the role of ERRalpha in PGC-1alpha signaling, a parallel approach of high-throughput screening and gene-expression analysis was used to identify ERRalpha small-molecule regulators and target genes. We report here the identification of a potent and selective ERRalpha inverse agonist that interferes effectively with PGC-1alpha/ERRalpha-dependent signaling. This inverse agonist inhibits the constitutive activity of ERRalpha in both biochemical and cell-based assays. Also, we demonstrate that monoamine oxidase B is an ERRalpha target gene whose expression is regulated by PGC-1alpha and ERRalpha and inhibited by the ERRalpha inverse agonist. The discovery of potent and selective ERRalpha modulators and their effect on PGC-1alpha signaling provides mechanistic insight into gene regulation by PGC-1alpha. These findings validate ERRalpha as a promising therapeutic target in the treatment of metabolic disorders, including diabetes and obesity.
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PMID:Regulation of PPARgamma coactivator 1alpha (PGC-1alpha) signaling by an estrogen-related receptor alpha (ERRalpha) ligand. 1518 75

The obesity epidemic in industrialized countries is associated with increases in cardiovascular disease (CVD) and certain types of cancer. In animal models, caloric restriction (CR) suppresses these diseases as well as chemical-induced tissue damage. These beneficial effects of CR overlap with those altered by agonists of nuclear receptors (NR) under control of the fasting-responsive transcriptional co-activator, peroxisome proliferator-activated co-activator 1alpha (PGC-1alpha). In a screen for compounds that mimic CR effects in the liver, we found statistically significant overlaps between the CR transcript profile in wild-type mice and the profiles altered by agonists of lipid-activated NR, including peroxisome proliferator-activated receptor alpha (PPARalpha), liver X receptor, and their obligate heterodimer partner, retinoid X receptor. The overlapping genes included those involved in CVD (lipid metabolism and inflammation) and cancer (cell fate). Based on this overlap, we hypothesized that some effects of CR are mediated by PPARalpha. As determined by transcript profiling, 19% of all gene expression changes in wild-type mice were dependent on PPARalpha, including Cyp4a10 and Cyp4a14, involved in fatty acid omega-oxidation, acute phase response genes, and epidermal growth factor receptor but not increases in PGC-1alpha. CR protected the livers of wild-type mice from damage induced by thioacetamide, a liver toxicant and hepatocarcinogen. CR protection was lost in PPARalpha-null mice due to inadequate tissue repair. These results demonstrate that PPARalpha mediates some of the effects of CR and indicate that a pharmacological approach to mimicking many of the beneficial effects of CR may be possible.
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PMID:Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors. 1530 62

PGC-1alpha is a coactivator of nuclear receptors and other transcription factors that regulates several metabolic processes, including mitochondrial biogenesis and respiration, hepatic gluconeogenesis, and muscle fiber-type switching. We show here that, while hepatocytes lacking PGC-1alpha are defective in the program of hormone-stimulated gluconeogenesis, the mice have constitutively activated gluconeogenic gene expression that is completely insensitive to normal feeding controls. C/EBPbeta is elevated in the livers of these mice and activates the gluconeogenic genes in a PGC-1alpha-independent manner. Despite having reduced mitochondrial function, PGC-1alpha null mice are paradoxically lean and resistant to diet-induced obesity. This is largely due to a profound hyperactivity displayed by the null animals and is associated with lesions in the striatal region of the brain that controls movement. These data illustrate a central role for PGC-1alpha in the control of energy metabolism but also reveal novel systemic compensatory mechanisms and pathogenic effects of impaired energy homeostasis.
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PMID:Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. 1545 76

The estrogen-related receptor alpha (ERRalpha) is an orphan member of the superfamily of nuclear receptors involved in the control of energy metabolism. In particular, ERRalpha induces a high energy expenditure in the presence of the coactivator PGC-1alpha. However, ERRalpha knockout mice have reduced fat mass and are resistant to diet-induced obesity. ERRalpha is expressed in epithelial cells of the small intestine, and because the intestine is the first step in the energy chain, we investigated whether ERRalpha plays a function in dietary energy handling. Gene expression profiling in the intestine identified a subset of genes involved in oxidative phosphorylation that were down-regulated in the absence of ERRalpha. In support of the physiological role of ERRalpha in this pathway, isolated enterocytes from ERRalpha knockout mice display lower capacity for beta-oxidation. Microarray results also show altered expression of genes involved in dietary lipid digestion and absorption, such as pancreatic lipase-related protein 2 (PLRP2), fatty acid-binding protein 1 and 2 (L-FABP and I-FABP), and apolipoprotein A-IV (apoA-IV). In agreement, we found that ERRalpha-/- pups exhibit significant lipid malabsorption. We further show that the apoA-IV promoter is a direct target of ERRalpha and that its presence is required to maintain basal level but not feeding-induced regulation of the apoA-IV gene in mice. ERRalpha, in cooperation with PGC-1alpha, activates the apoA-IV promoter via interaction with the apoC-III enhancer in both human and mouse. Our results demonstrate that apoA-IV is a direct ERRalpha target gene and suggest a function for ERRalpha in intestinal fat transport, a crucial step in energy balance.
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PMID:Estrogen-related receptor alpha (ERRalpha) is a transcriptional regulator of apolipoprotein A-IV and controls lipid handling in the intestine. 1546 64

Excessive accumulation of triglycerides and certain fatty acid derivatives in skeletal muscle and other tissues appears to mediate many of the adverse effects of insulin resistance syndrome. Although fatty diets and obesity can promote such accumulation, deficient capacity for fatty acid oxidation can also contribute in this regard. Indeed, in subjects who are insulin resistant, diabetic, and/or obese, fatty acid oxidation by skeletal muscle tends to be inefficient, reflecting decreased expression of mitochondria and mitochondrial enzymes in muscle. This phenomenon is not corrected by weight loss, is not simply reflective of subnormal physical activity, and is also seen in lean first-degree relatives of diabetics; thus, it appears to be primarily attributable to genetic factors. Recent studies indicate that decreased expression of PPARgamma coactivator-1alpha (PGC-1alpha), a "master switch" which induces mitochondrial biogenesis by supporting the transcriptional activity of the nuclear respiratory factors, may largely account for the diminished oxidative capacity of subjects prone to insulin resistance. Thus, feasible measures which up-regulate PGC-1alpha may be useful for preventing and treating insulin resistance and obesity. These may include exercise training, metformin and other agents which stimulate AMP-activated kinase, high-dose biotin, and PPARdelta agonists. Drugs which are specific agonists for PPARdelta show remarkable efficacy in rodent models of insulin resistance, diabetes, and obesity, and are currently being evaluated clinically. Phytanic acid, a branched-chain fatty acid found in omnivore diets, can also activate PPARdelta, and thus should be examined with respect to its impact on mitochondrial biogenesis and insulin sensitivity.
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PMID:Up-regulation of PPARgamma coactivator-1alpha as a strategy for preventing and reversing insulin resistance and obesity. 1560 77


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