PPAR  and human metabolic disease

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.

PPARs and adipocyte function

“…Finally, as mentioned above, point mutations in the ligand or DNA-binding domain of PPAR are associated with severe insulin resistance in human subjects [26,27]. The majority of data also supports the conclusion that WAT is the principal tissue responsible for the therapeutic effects of TZDs although extra-adipose actions also contribute to improved insulin sensitivity.…”

“…Naturally occurring PPAR mutations in human subjects also support an important role for this transcription factor in WAT development [26,27]. Specifically, individuals carrying dominant-negative mutations in PPAR display partial lipodystrophy concomitant with insulin resistance, dys-lipidaemia, and hypertension.…”

“…Reciprocally, PPAR agonist treatment in humans leads to peripheral redistribution of WAT [27]. Finally, mice harbouring dominant negative PPAR mutations similarly exhibit altered fat pad distribution (albeit one characterised by decreased intra-abdominal relative to extra-abdominal WAT) [28,29] indicating that PPAR also plays a role in determining WAT distribution.…”

“…In this respect, despite a fairly moderate degree of lipodystrophy these subjects often display extreme hyper-triglyceridaemia [27].…”

Variation in the peroxisome proliferator-activated receptor δ gene in relation to common metabolic traits in 7,495 middle-aged white people

“…Three subtypes, α, γ and δ, have been identified, with distinct roles in metabolism. PPARα is a regulator of fatty acid oxidation, primarily produced in the liver [2], whereas PPARγ mainly functions as a regulator of adipogenesis [3]. In recent years, PPARδ has emerged as a key player in the regulation of energy metabolism and as a potential novel drug target.…”