Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewPPARγ in human and mouse physiology
Introduction
Peroxisome proliferator-activated receptor-gamma (PPARγ, NR1C3) belongs to a nuclear receptor superfamily of transcription factors. It is mainly known to regulate adipocyte differentiation and fatty-acid uptake and storage (reviewed in [1], [2], [3]). The two distinct isoforms of PPARγ protein, PPARγ1 and PPARγ2, originate from one PPARγ gene through the use of separate promoters and 5′ exons (Fig. 1), and differ by the presence of an extra 28 (human)–30 (mouse) amino acids at the NH2-terminal end of PPARγ2 [4], [5], [6], [7], [8], [9], [10]. This extension of the ligand-independent activation domain makes PPARγ2 a better transcriptional activator relative to PPARγ1 [11]. Not only the protein structure of PPARγ1 and 2 is different but both isoforms show also a distinct expression pattern. PPARγ2 expression is mainly limited to the adipose tissue whereas PPARγ1 is ubiquitously expressed [12], [13]. The transcriptional activity of PPARγ is controlled by the promiscuous binding of small lipophilic ligands into the ligand-binding pocket. Although a natural compound exhibiting specific, high-affinity binding characteristics remains unidentified, endogenous polyunsaturated fatty acids and eicosanoids, derived from nutrition or metabolic pathways, have been recognized as ligands for PPARγ [14], [15], [16]. In addition, many synthetic compounds, most particularly the thiazolidinediones (TZDs), are potent PPARγ agonists (reviewed in [17], [18]).
Human metabolism is evolutionarily equipped to cope with pre-agricultural cycles of feast and famine, and physical activity and rest. Because of the rapid emergence of the modern westernized life-style, exposing people to chronically elevated levels of natural PPARγ ligands and positive energy balance, our genetic makeup has become ill adapted to cope with our lifestyle [19], [20], [21]. The continual PPARγ activation promotes adipogenesis and fatty-acid storage, and eventually obesity and associated metabolic diseases such as hyperlipidemia, insulin resistance, type 2 diabetes mellitus (T2DM) and cardiovascular diseases including hypertension, which constitute a heavy social and economic burden. Among the most potent current treatment strategies for T2DM are the TZDs which exert their antidiabetic effects by sensitizing the body to insulin's action. However, the clinical use of these full PPARγ agonists is limited by weight gain due to increased adiposity, fluid retention, and heart failure in up to 15% of patients [22], [23], [24]. In addition, despite their fairly wide use, the long-term adverse effects of TZDs are not very well known, and they may increase the risk for osteoporosis [25], [26] and colon cancer [27], [28].
In this review we summarize the studies that have shed new light on the role of PPARγ in energy homeostasis not only in the main metabolic tissues i.e. adipose tissue, liver and skeletal muscle, but also in other tissues. The reviewed studies also emphasize that insulin sensitization can be achieved without concomitant increase in fat deposition by modulating PPARγ activity. In addition to obesity, altered PPARγ activity, elicited by our westernized lifestyle, has potentially influenced bone homeostasis, longevity, cardiovascular and kidney function and cancer risk, as recent literature supports a significant role for PPARγ in these processes. Furthermore, animal models with altered PPARγ activity have elucidated the distinct roles of PPARγ in various tissues, as well as PPARγ-dependent and independent actions of TZDs therein. We can introduce here only a fraction of the existing information on this nuclear factor, and will thus mostly concentrate on the lessons learned from the study of various natural or engineered genetic variants of PPARγ that have altered PPARγ activity.
Section snippets
Human PPARγ genetic variants
The vital role of PPARγ in adipogenesis began to emerge more than a decade ago [12] and has remained undisputed since. Both of the processes central in adipogenesis, namely preadipocyte differentiation and fatty acid storage in mature adipocytes, are controlled by PPARγ, and particularly the PPARγ2 isoform (reviewed in [2], [3], [20], [21]). Genetic association studies in humans underscore the role for PPARγ in adipogenesis as well as the complexity of PPARγ biology. One of the first links was
Mouse genetic variants
PPARγ exerts pleiotropic functions in a wide range of tissues and in processes beyond metabolism. Genetic manipulations in the mouse offer excellent opportunities to unravel the complex physiological effects of altered PPARγ activity in a well-controlled genetic background and environmental setting. First came the generation of a conventional PPARγ deficient mice which, unfortunately, die in utero due to major placental and cardiac defects. Although a single PPARγ−/− animal was rescued by
PPARγ and bone homeostasis
Physical activity is a prerequisite for food procurement, food is a prerequisite for energy storage, and stored energy is a prerequisite for physical activity. Because of this inextricable linkage, it is plausible that concomitant with the role PPARγ has in fuel storage and use, it also regulates bone mass to provide the structural strength required in procuring the next meal. Further link between energy storage and bone arises from the fact that both adipocytes, whose differentiation PPARγ
PPARγ and longevity
Obesity is accompanied by insulin resistance, hyperlipidemia and T2DM which are risk factors for many other diseases that are likely to shorten lifespan. On the other hand, also lipodystrophy is known to shorten lifespan and it results in complications surprisingly similar to those seen in obesity, both in mice and humans (reviewed in [133], [134]). Conversely, caloric restriction promotes longevity and is accompanied by reduced fat mass and improved insulin sensitivity (reviewed in [135], [136]
Human PPARγ mutations in the mouse
Mouse models carrying specific PPARγ mutations have been generated to further refine the information gained from the whole-body and tissue-specific deletions of PPARγ. First such model was the knock-in of alanine at position 112 (S112A) which prevents serine phosphorylation and renders PPARγ constitutively active, thus resembling but not replicating the human Pro115Gln mutation [144]. In mice this mutation preserves insulin sensitivity during diet-induced obesity due to undersized adipocytes,
Conclusions and perspectives
The phenotypic effects of human PPARγ variants and various mouse models with modified PPARγ expression levels unequivocally demonstrate the highly complex nature of PPARγ biology. Despite occasionally confusing results, accumulating evidence confirms the critical role for PPARγ in adipogenesis, maintenance of glucose and lipid metabolism, bone homeostasis, and control of inflammation and blood pressure. The specific roles for PPARγ in each tissue are also emerging, as adipogenesis is regulated
Acknowledgments
This work was supported by grants from CNRS, INSERM, Hopitaux Universitaires de Strasbourg, Academy of Finland, EU, EMBO and NIH (DK67320). We thank the members of the Auwerx Laboratory for helpful discussions.
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