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      The Mechanisms of Action of PPARs

      1 , 1
      Annual Review of Medicine
      Annual Reviews

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          Abstract

          The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPAR gamma, PPAR alpha, and PPAR delta, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases.

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          Adiponectin is a novel, adipose-specific protein abundantly present in the circulation, and it has antiatherogenic properties. We analyzed the plasma adiponectin concentrations in age- and body mass index (BMI)-matched nondiabetic and type 2 diabetic subjects with and without coronary artery disease (CAD). Plasma levels of adiponectin in the diabetic subjects without CAD were lower than those in nondiabetic subjects (6.6+/-0.4 versus 7.9+/-0.5 microg/mL in men, 7.6+/-0.7 versus 11.7+/-1.0 microg/mL in women; P<0.001). The plasma adiponectin concentrations of diabetic patients with CAD were lower than those of diabetic patients without CAD (4.0+/-0.4 versus 6.6+/-0.4 microg/mL, P<0.001 in men; 6.3+/-0.8 versus 7.6+/-0. 7 microg/mL in women). In contrast, plasma levels of leptin did not differ between diabetic patients with and without CAD. The presence of microangiopathy did not affect the plasma adiponectin levels in diabetic patients. Significant, univariate, inverse correlations were observed between adiponectin levels and fasting plasma insulin (r=-0.18, P<0.01) and glucose (r=-0.26, P<0.001) levels. In multivariate analysis, plasma insulin did not independently affect the plasma adiponectin levels. BMI, serum triglyceride concentration, and the presence of diabetes or CAD remained significantly related to plasma adiponectin concentrations. Weight reduction significantly elevated plasma adiponectin levels in the diabetic subjects as well as the nondiabetic subjects. These results suggest that the decreased plasma adiponectin concentrations in diabetes may be an indicator of macroangiopathy.
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            Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance

            Tumor necrosis factor-alpha (TNF-alpha) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-alpha messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-alpha protein was also elevated locally and systemically. Neutralization of TNF-alpha in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.
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              A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis.

              Adaptive thermogenesis is an important component of energy homeostasis and a metabolic defense against obesity. We have cloned a novel transcriptional coactivator of nuclear receptors, termed PGC-1, from a brown fat cDNA library. PGC-1 mRNA expression is dramatically elevated upon cold exposure of mice in both brown fat and skeletal muscle, key thermogenic tissues. PGC-1 greatly increases the transcriptional activity of PPARgamma and the thyroid hormone receptor on the uncoupling protein (UCP-1) promoter. Ectopic expression of PGC-1 in white adipose cells activates expression of UCP-1 and key mitochondrial enzymes of the respiratory chain, and increases the cellular content of mitochondrial DNA. These results indicate that PGC-1 plays a key role in linking nuclear receptors to the transcriptional program of adaptive thermogenesis.
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                Author and article information

                Journal
                Annual Review of Medicine
                Annu. Rev. Med.
                Annual Reviews
                0066-4219
                1545-326X
                February 2002
                February 2002
                : 53
                : 1
                : 409-435
                Affiliations
                [1 ]Department of Molecular Endocrinology, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065; e-mail:
                Article
                10.1146/annurev.med.53.082901.104018
                11818483
                6503e2e9-2765-447a-a44e-8e4f04c6445c
                © 2002
                History

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