PPARδ as a therapeutic target in metabolic disease

Department of Genetics and Complex Diseases, Harvard University School of Public Health, 665 Huntington Avenue, Bldg 2, Room 119, Boston, MA 02115-5818, USA.
FEBS Letters (Impact Factor: 3.17). 02/2008; 582(1):26-31. DOI: 10.1016/j.febslet.2007.11.040
Source: PubMed


PPAR delta is the only member in the PPAR subfamily of nuclear receptors that is not a target of current drugs. Animal studies demonstrate PPAR delta activation exerts many favorable effects, including reducing weight gain, increasing skeletal muscle metabolic rate and endurance, improving insulin sensitivity and cardiovascular function and suppressing atherogenic inflammation. These activities stem largely from the ability of PPAR delta to control energy balance, reduce fat burden and protect against lipotoxicity caused by ectopic lipid deposition. Therefore, PPAR delta represents a novel therapeutic target and the development of PPAR delta gonists/modulators may be useful for treating the whole spectrum of metabolic syndrome.

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Available from: Chih-Hao Lee, Jun 23, 2014
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    • "PPARβ/δ is expressed in organs/cells highly associated with fatty acid catabolism such as hepatocytes in the liver [Sanderson et al., 2010; Sanderson et al., 2009; Shan et al., 2008], adipocytes in the brown and white adipose tissue (BAT and WAT) [Leibowitz et al., 2000; Mottillo et al., 2012; Pan et al., 2009; Reilly and Lee, 2008; Roberts et al., 2011; Wang et al., 2003] and skeletal muscle cells [Giordano et al., 2009]. "
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    ABSTRACT: The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that function as transcription factors regulating the expression of genes involved in cellular differentiation, development, metabolism and also tumorigenesis. Three PPAR isotypes (α, β/δ and γ) have been identified, among which PPARβ/δ is the most difficult to functionally examine due to its tissue-specific diversity in cell fate determination, energy metabolism and housekeeping activities. PPARβ/δ acts both in a ligand-dependent and -independent manner. The specific type of regulation, activation or repression, is determined by many factors, among which the type of ligand, the presence/absence of PPARβ/δ-interacting corepressor or coactivator complexes and PPARβ/δ protein post-translational modifications play major roles. Recently, new global approaches to the study of nuclear receptors have made it possible to evaluate their molecular activity in a more systemic fashion, rather than deeply digging into a single pathway/function. This systemic approach is ideally suited for studying PPARβ/δ, due to its ubiquitous expression in various organs and its overlapping and tissue-specific transcriptomic signatures. The aim of the present review is to present in detail the diversity of PPARβ/δ function, focusing on the different information gained at the systemic level, and describing the global and unbiased approaches that combine a systems view with molecular understanding.
    Nuclear Receptor Signaling 04/2015; 13. DOI:10.1621/nrs.13001
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    • "metabolism and glucose homeostasis (Braissant et al., 1996; Wang et al., 2003). PPARβ has been shown to increase fat oxidation and reduce lipid accumulation in adipose tissue and in other tissues (Reilly and Lee, 2008). Furthermore, studies in rodents have shown that activation of PPAR-β reduces body weight, increases metabolic rate and improves insulin sensitivity, through increased skeletal muscle fatty acid oxidation (Wang et al., 2003). "
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    ABSTRACT: We analyzed the effects of the peroxisome proliferator-activated receptor β/δ (PPAR-β) agonists, GW0742 and L165041, on the impaired insulin signaling induced by high glucose in human umbilical vein endothelial cells (HUVECs) and aorta and mesenteric arteries from diabetic rats. Insulin-stimulated NO production, Akt-Ser473 and eNOS-Ser1177 phosphorylation, and reactive oxygen species (ROS) production were studied in HUVECs incubated in low or high glucose medium. Insulin-stimulated relaxations and protein phosphorylation in vessel from streptozotocin (STZ)-induced diabetic rats were also analyzed. HUVECs incubated in high glucose medium showed a significant reduction of the insulin-stimulated production of NO. High glucose also reduced insulin-induced Akt-Ser473 and eNOS-Ser1177 phosphorylation, increased IRS-1-Ser636 and ERK1/2-Thr183-Tyr185 phosphorylation and increased ROS production. The coincubation with the PPAR-β agonists GW0742 or L165041 prevented all the effects induced by high glucose. In turn, the effects induced by the agonists were suppressed when HUVEC were also incubated with the PPAR-β antagonist GSK0660, the piruvate dehydrogenase kinase (PDK)-4 inhibitor dichloroacetate or after knockdown of both PPAR-β and PDK4 with siRNA. The ERK1/2 inhibitor PD98059, the ROS scavenger catalase, the inhibitor of complex II thenoyltrifluoroacetone or the uncoupler of oxidative phosphorylation, carbonyl cyanide m-chlorophenylhydrazone also prevented glucose-induced insulin resistance. In STZ diabetic rats, oral GW0742 also improved insulin signaling and the impaired NO-mediated vascular relaxation. PPAR-β activation in vitro and in vivo restores the endothelial function, preserving the insulin-Akt-eNOS pathway impaired by high glucose, at least in part, through PDK4 activation.
    British Journal of Pharmacology 02/2014; 171(12). DOI:10.1111/bph.12646 · 4.84 Impact Factor
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    • "Several synthetic ligands have also been developed, to improve symptoms of metabolic disorders [122] [123]. Experimental data support that the combined hepatic and muscular effects of PPARβ/δ constitute a " fatty acid futile cycle, " resulting in improved glucose and lipid metabolism [124]. "
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    ABSTRACT: Reactive oxygen species, when released in controlled conditions and limited amounts, contribute to cellular proliferation, senescence and survival by acting as signalling intermediates. In the last decades there has been an epidemic diffusion of Non-alcoholic Fatty Liver Disease (NAFLD), that represents the result of the impairment of lipid metabolism, redox unbalance and insulin resistance in the liver. To date, most studies and reviews have been focused on the molecular mechanisms by which fatty liver progresses to steatohepatitis, but the leading processes to the development of hepatic steatosis in NAFLD are not fully understood yet. Several nuclear receptors, such as peroxisome proliferator-activated receptors α/γ/δ (PPAR α/γ/δ), PPARγ co-activators-1α and 1β (PGC-1 α/β), sterol regulatory element-binding proteins (SREBPs), AMP-activated protein kinase (AMPK), liver-X-receptors (LXRs) and farnesoid-X-receptor (FXR), play key roles in the regulation of lipid homeostasis during the pathogenesis of NAFLD. These nuclear receptors may act as redox sensors and may modulate different metabolic pathways in response to specific molecules which act as ligands. It is conceivable that a redox-dependent modulation of lipid metabolism, nuclear receptor-mediated, could cause the development of hepatic steatosis and insulin resistance. Thus, this network may represent a potential therapeutic target for the treatment and prevention of hepatic steatosis and its progression to steatohepatitis. This review summarizes the redox-dependent factors that contribute to the metabolism alterations of fatty liver with a focus on the redox control of nuclear receptors in normal liver as well as in NAFLD.
    Free Radical Biology and Medicine 08/2013; 65. DOI:10.1016/j.freeradbiomed.2013.08.174 · 5.74 Impact Factor
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