The Roles of Peroxisome Proliferator-Activated Receptors in the Metabolic Syndrome

Dec 31, 2013Progress in molecular biology and translational science

How peroxisome proliferator-activated receptors relate to metabolic syndrome

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Abstract

New PPAR drugs targeting multiple subtypes are in development to address metabolic syndrome.

Obesity is linked to insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively termed metabolic syndrome.
PPARs (alpha, beta, and gamma) play significant roles in regulating lipid and glucose metabolism.
Current treatments include fibrate drugs for PPARα and thiazolidinediones for PPARγ, but no drugs exist for PPARβ.
Clinical use of TZDs has revealed side effects, prompting interest in developing safer PPAR-targeting drugs.
Innovative PPAR drugs include partial, dual, or pan agonists, antagonists, and selective modulators.

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The epidemic of obesity and its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X, is one of the most challenging health problems facing industrialized countries. The nuclear receptors, peroxisome proliferator-activated receptors (PPARs alpha (α), beta (β) also known as delta (δ), and gamma (γ)), have well-documented roles in lipid and glucose metabolism. Pharmacologically, PPARα is activated by fibrate hypolipidemic drugs, whereas PPARγ is activated by insulin sensitizers thiazolidinediones (TZDs). No marketed drug is yet available for PPARβ(δ). The identification of fibrates and TZDs as respective ligands for PPARα and PPARγ was a groundbreaking finding that sparked notable pharmaceutical interest in PPARs as potential drug targets for treatment of the metabolic syndrome. Limiting side effects associated with clinical use of TZDs have emerged in recent years. New and novel PPAR drugs with broad safety margins and therapeutic potentials for the metabolic syndrome are in development. These include partial, dual, or pan PPAR agonists; PPAR antagonists; and selective PPAR modulators. The objective of this chapter is to highlight the therapeutic benefits of targeting more than one PPAR subtype in the treatment of the metabolic syndrome. The pros and cons observed during clinical use of TZDs and the strategies and progress made in the production of new generations of safe and effective PPAR ligands are discussed.

The Roles of Peroxisome Proliferator-Activated Receptors in the Metabolic Syndrome

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