PPARs: therapeutic targets for metabolic disease

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The three peroxisome-proliferator-activated receptor (PPAR) subtypes, PPAR-γ, PPAR-α and PPAR-δ, are nuclear receptors that have been the focus of extensive research during the past decade. These receptors function as lipid sensors that coordinately regulate the expression of large gene arrays and, thereby, modulate important metabolic events. They are also the targets of drugs that are effective in the treatment of metabolic disorders (type 2 diabetes mellitus and atherosclerosis) that afflict industrialized societies at epidemic levels. Ongoing research indicates that modulation of PPAR activity might be an effective therapy for additional maladies associated with the metabolic syndrome, including obesity. Novel PPAR ligands are now being developed that possess broader efficacies and improved tolerability compared with currently available therapeutic agents.

Section snippets

Nuclear receptor targets for the treatment of metabolic disorders

The three peroxisome-proliferator-activated receptor (PPAR) subtypes, PPAR-γ, PPAR-α and PPAR-δ (also known as PPAR-β), constitute a subfamily of nuclear receptors [1]. These lipid sensors are ‘master’ transcriptional regulators of nutrient metabolism and energy homeostasis that modulate the expression of unique constellations of genes. PPARs form obligate heterodimers with another nuclear receptor, the retinoid X receptor, which bind to peroxisome proliferator response elements (PPREs) that

Adipocytes

PPAR-γ is present in high concentrations in adipocytes [5]. Seminal studies in vitro have demonstrated that this receptor is both necessary and sufficient for adipocyte differentiation, and that it promotes lipid accumulation by adipocytes [6]. The importance of PPAR-γ in adipocyte biology is underscored further by studies in vivo in which adipose-specific ablation of PPAR-γ expression in mice results in adipocyte hypocellularity [7], and heterozygous PPAR-γ knockout mice have reduced adiposity

Lipid metabolism

PPAR-α is expressed highly in liver, heart and skeletal muscle, tissues that extract a high level of their energy requirements from lipids. [50]. During prolonged fasting that results in hypoglycemia, fatty acids are released from fat depots and travel to the liver where they are taken up, oxidized and metabolized into ketone bodies to provide fuel for peripheral tissues. The crucial role of PPAR-α in mediating these metabolic processes and, ultimately, energy homeostasis is demonstrated by the

Pharmacology

Because of its ubiquitous expression and the paucity of selective ligands, PPAR-δ is the least understood PPAR subtype. Nevertheless, early PPAR-δ-selective agonists were found to elevate HDL-C levels in diabetic mice [69], a seminal observation that indicated that PPAR-δ ligands might have beneficial effects on dyslipidemia. Subsequently, the potent PPAR-δ agonist GW501516 (see Chemical names) was shown to increase HDL-C while decreasing elevated TG and insulin levels in obese rhesus monkeys

Selective PPAR-γ modulators

Although the TZDs rosiglitazone and pioglitazone, which are full agonists of PPAR-γ, have significant clinical anti-diabetic efficacy, their use is associated with adverse events including plasma-volume expansion, hemodilution, edema, increased adiposity and weight gain [74]. In addition, TZDs induce cardiomegaly (cardiac enlargement) in some preclinical species 75, 76. These undesirable effects, and the potential to cause congestive heart failure in the considerable subset of diabetic patients

PPAR-α/γ dual agonists and PPAR-α/γ/δ pan agonists

Generally, T2DM patients suffer from both hyperglycemia and dyslipidemia. Clinical studies implicate hyperglycemia in the onset of microangiopathic complications of T2DM, including kidney failure, retinopathy and peripheral neuropathy. However, the major cause of mortality in T2DM patients is atherosclerotic macrovascular disease, which culminates in myocardial infarction. Such cardiovascular disease appears to result, in large part, from diabetic dyslipidemia. Regrettably, although currently

Concluding remarks

The ability of PPARs to mediate many metabolic and therapeutic actions have made them a central focus of pharmacological and genetic research for more than a decade. Through this effort, the PPARs have been shown to coordinately regulate the expression of a vast array of genes including those that control nutrient metabolism, energy homeostasis, insulin signaling, inflammation and cell differentiation. In the clinic, PPAR-γ agonists are effective in treating T2DM patients, and PPAR-α agonists

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