J Clin Invest 116(3): 581-589

PPARγ and human metabolic disease

^{Department of Clinical Biochemistry and}^{Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom.}

Address correspondence to: S. O’Rahilly, Department of Clinical Biochemistry, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom. Phone: 44-122-333-6855; Fax: 44-122-333-0598; E-mail: ku.ca.mac.lhcsdem@401os. Or to: V.K.K. Chatterjee, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom. Phone: 44-1223-336-842; Fax: 44-1223-336-846; E-mail: ku.ca.mac.oib.elom@1ckk.

Abstract

The nuclear receptor family of PPARs was named for the ability of the original member to induce hepatic peroxisome proliferation in mice in response to xenobiotic stimuli. However, studies on the action and structure of the 3 human PPAR isotypes (PPARα, PPARδ, and PPARγ) suggest that these moieties are intimately involved in nutrient sensing and the regulation of carbohydrate and lipid metabolism. PPARα and PPARδ appear primarily to stimulate oxidative lipid metabolism, while PPARγ is principally involved in the cellular assimilation of lipids via anabolic pathways. Our understanding of the functions of PPARγ in humans has been increased by the clinical use of potent agonists and by the discovery of both rare and severely deleterious dominant-negative mutations leading to a stereotyped syndrome of partial lipodystrophy and severe insulin resistance, as well as more common sequence variants with a much smaller impact on receptor function. These may nevertheless have much greater significance for the public health burden of metabolic disease. This Review will focus on the role of PPARγ in human physiology, with specific reference to clinical pharmacological studies, and analysis of PPARG gene variants in the abnormal lipid and carbohydrate metabolism of the metabolic syndrome.

Abstract

Acknowledgments

V.K.K. Chatterjee and S. O’Rahilly are supported by the Wellcome Trust.

Acknowledgments

Footnotes

Nonstandard abbreviations used: FA, fatty acid; PLRS, PPARγ ligand resistance syndrome; TG, triglyceride; TZD, thiazolidinedione.

Conflict of interest: R.K. Semple and V.K.K. Chatterjee have no conflict of interest. S. O’Rahilly has received research grant support from GlaxoSmithKline, manufacturer of rosiglitazone.

Footnotes

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