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: 3.34). 02/2008; 582(1):26-31. DOI: 10.1016/j.febslet.2007.11.040
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Chih-Hao Lee, Jun 23, 2014
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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; DOI:10.1111/bph.12646 · 4.99 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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 · 5.71 Impact Factor
  • Source
    • "PGC-1α also regulates genes involved in oxidative metabolism and mitochondrial biogenesis by activating transcription factors (Lin et al., 2005), including PPARs. The PPAR nuclear receptor (NR) family consists of PPARα, PPARδ (also called PPARβ) and PPARγ, all of which are drug targets for components of metabolic syndrome (Lee et al., 2003; Reilly and Lee, 2008). PPARα and PPARγ exhibit more restricted effects on fatty acid β-oxidation and fat storage in the liver and adipocyte, respectively. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The transcriptional corepressor SMRT utilizes two major receptor-interacting domains (RID1 and RID2) to mediate nuclear receptor (NR) signaling through epigenetic modification. The physiological significance of such interaction remains unclear. We find SMRT expression and its occupancy on peroxisome proliferator-activated receptor (PPAR) target gene promoters are increased with age in major metabolic tissues. Genetic manipulations to selectively disable RID1 (SMRT(mRID1)) demonstrate that shifting SMRT repression to RID2-associated NRs, notably PPARs, causes premature aging and related metabolic diseases accompanied by reduced mitochondrial function and antioxidant gene expression. SMRT(mRID1) cells exhibit increased susceptibility to oxidative damage, which could be rescued by PPAR activation or antioxidant treatment. In concert, several human Smrt gene polymorphisms are found to nominally associate with type 2 diabetes and adiponectin levels. These data uncover a role for SMRT in mitochondrial oxidative metabolism and the aging process, which may serve as a drug target to improve health span.
    Cell metabolism 12/2010; 12(6):643-53. DOI:10.1016/j.cmet.2010.11.007 · 16.75 Impact Factor
Show more