Minireview: PPARγ as the target of obesogens

Abstract

The peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of adipogenesis and is medically important for its connections to obesity and the treatment of type II diabetes. Activation of this receptor by certain natural or xenobiotic compounds has been shown to stimulate adipogenesis in vitro and in vivo. Obesogens are chemicals that ultimately increase obesity through a variety of potential mechanisms, including activation of PPARγ. The first obesogen for which a definitive mechanism of action has been elucidated is the PPARγ and RXR activator tributyltin; however, not all chemicals that activate PPARγ are adipogenic or correlated with obesity in humans. There are multiple mechanisms through which obesogens can target PPARγ that may not involve direct activation of the receptor. Ligand-independent mechanisms could act through obesogen-mediated post-translational modification of PPARγ which cause receptor de-repression or activation. PPARγ is active in multipotent stem cells committing to the adipocyte fate during fat cell development. By modifying chromatin structure early in development, obesogens have the opportunity to influence the promoter activity of PPARγ, or the ability of PPARγ to bind to its target genes, ultimately biasing the progenitor pool towards the fat lineage. Obesogens that act by directly or indirectly activating PPARγ, by increasing the levels of PPARγ protein, or enhancing its recruitment to promoters of key genes in the adipogenic pathway may ultimately play an important role in adipogenesis and obesity.

Introduction

A major advance in the study of adipocyte development was the discovery of genes specifically expressed in mature adipocytes. Among the first to be identified was the p422 protein [1], [2], later called aP2 (adipocyte protein 2) and now termed fatty acid binding protein (FABP4). Using FABP4 as a marker, it became possible to study how the differentiation of pre-adipocytes into adipocytes was regulated. Indeed, FABP4 expression is considered to be indicative of a cell committed to the adipocyte lineage [3]. An enhancer complex, termed adipocyte regulatory factor 6 (ARF6), was soon found to drive expression of FABP4 [4]. With biochemical and mass spectrometric methods, ARF6 was characterized as a heterodimer of the nuclear receptors PPARγ2 and RXR [5]. The RXR–PPARγ heterodimer is a key regulator of the adipogenic program and numerous PPARγ target genes have been identified [reviewed in [6], [7], [8]]. These include lipoprotein lipase (LPL), which generates non-esterified fatty acids (used in triglyceride synthesis) from lipoproteins, and aquaporin 7, which facilitates the transportation of glycerol, the backbone of triglycerides, into adipocytes [9]. During adipogenesis, PPARγ expression is positively reinforced by CCAATT enhancer binding protein alpha (C/EBPα) [10], the activity of which is modulated by PPARγ itself [10], glucocorticoid signaling [11], insulin signaling [12], as well as cAMP levels [13]. After the adipogenic program is initiated, insulin stimulates PPARγ- and C/EBPα-expressing cells to accumulate/store the lipid that they produce [14].

As is the case for nearly all nuclear hormone receptors, PPARγ can be perturbed by environmental chemicals. PPARγ is perhaps even more susceptible than most nuclear receptors because its ligand-binding pocket is large and can accommodate a diversity of chemical structures [15]. Since PPARγ is a master regulator of adipogenesis, a logical hypothesis is that inappropriate activation of the receptor contributes to obesity. Obesogens are chemicals, natural or xenobiotic, that promote obesity by increasing the number of fat cells, up-regulating fat storage into existing fat cells, changing the amount of calories burned at rest, shifting energy balance to favor storage of calories or altering the mechanisms through which the body regulates appetite and satiety. The first obesogen for which a definitive mechanism of action has been elucidated is the PPARγ and RXR activator, tributyltin [16], [17]. The most well known pharmaceutical obesogens, which are also agonists of PPARγ, are the thiazolidinediones (TZDs), such as rosiglitazone and pioglitazone, used to treat type 2 diabetes. TZDs are linked to weight gain in humans [18] and increased adipogenesis in cell culture [19]. Activation of PPARγ by TZDs increases proliferation of new fat cells, thereby reducing adipocyte hypertrophy, which has been associated with inflammation, oxidative stress, and insulin resistance [20]. Whether these newly generated adipocytes “crave” to be filled with lipid is uncertain. However, it is well established that obese humans have a higher than normal fat cell number [21]; thus the hypothesis that increased adipocyte number leads to obesity is plausible and needs to be tested.

Considering the existence of pharmaceutical obesogens such as TZDs and xenobiotic obesogens such as organotins, it is highly likely that other compounds, which can inappropriately activate PPARγ, will be obesogenic. The topic of obesogens and their potential mechanisms of action has been extensively reviewed in recent years [22], [23], [24], [25]. PPARs as the targets of environmental chemicals, particularly phthalates has also been recently reviewed [26], [27], [28]. Therefore, this minireview focuses on recent evidence linking endocrine disrupting chemicals to PPARγ in particular and examines the molecular mechanisms through which they might act.