Peroxisome proliferator-activated receptor γ in diabetes and metabolism

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Abstract

The peroxisome proliferator-activated receptor γ (PPAR-γ) has been the focus of intense research during the past decade because ligands for this receptor have emerged as potent insulin sensitizers used in the treatment of type 2 diabetes. Recent advances include the discovery of novel genes that are regulated by PPAR-γ, which helps explain how activation of this adipocyte-predominant transcription factor regulates glucose and lipid homeostasis. Increased levels of circulating free fatty acids and lipid accumulation in non-adipose tissue have been implicated in the development of insulin resistance. This situation is improved by PPAR-γ ligands, which promote fatty acid storage in fat depots and regulate the expression of adipocyte-secreted hormones that impact on glucose homeostasis. The net result of the pleiotropic effects of PPAR-γ ligands is improvement of insulin sensitivity, although undesired side-effects limit the utility of this therapy. It might be possible to dissociate the anti-diabetic and adverse effects through selective modulation of PPAR-γ activity.

Section snippets

Insulin sensitizers and peroxisome proliferator-activated receptor γ (PPAR-γ)

Thiazolidinediones (TZDs) comprise a class of recently available pharmaceutical therapies for type 2 DM that reverse insulin resistance in target tissues, which is a major defect in this disease [8]. The first clinically used agent in this class, troglitazone, is no longer available clinically because of rare but life-threatening hepatic toxicity; however, its successors, the TZDs rosiglitazone and pioglitazone, have not been causally linked with this devastating side-effect [9]. In 2001, >15

PPAR-γ activation and insulin sensitivity: cause and effect

Several lines of evidence suggest that PPAR-γ activation causes insulin sensitization. First, the in vitro binding affinity of TZD ligands to PPAR-γ correlates well with their in vivo potency as insulin sensitizers 22, 23. Second, this relationship with PPAR-γ activation is shared by other ligands that are not structurally related to TZDs [22]. Third, retinoid X receptor (RXR) ligands, which can activate the PPAR-γ–RXR heterodimer, also have insulin-sensitizing effects in rodents [24]. Fourth,

Adipose is a major target tissue of insulin-sensitizing PPAR-γ ligands

PPAR-γ expression is dramatically higher in fat than in liver and, in particular, muscle 30, 31. However, improved glucose homeostasis related to administration of PPAR-γ ligands such as TZDs involves insulin sensitization in muscle and liver [32]. Adipose tissue accounts for only a small fraction of insulin-dependent glucose clearance [33]. Nevertheless, a crucial role of PPAR-γ in adipose tissue is suggested by the observation that mice lacking adipose tissue are refractory to the

PPAR-γ ligands modulate the endocrine functions of adipose tissue

The likelihood that PPAR-γ in adipose tissue is a major target of drugs such as TZDs that enhance insulin action in muscle and liver suggests that this transcription factor regulates the expression of genes involved in adipose signaling to other tissues. In addition to its well-known role as a sink and source of energy during feast and famine, respectively, adipose tissue has become firmly established as an endocrine organ during the past decade [38]. Adipocyte-derived leptin is a circulating

PPAR-γ ligand regulation of genes encoding adipocyte hormones

In addition to its other functions, leptin has insulin-sensitizing functions that are most apparent in the setting of lipoatrophy-associated insulin resistance, which is corrected by leptin administration 42, 43. PPAR-γ ligands, however, decrease leptin gene expression 44, 45. Leptin is therefore unlikely to be a major mediator of insulin sensitivity induced by PPAR-γ ligands. By contrast, TZDs repress adipocyte gene expression of resistin 46, 47, 48, TNF-α [49] and IL-6 [50], all of which have

PPAR-γ ligand regulation of genes affecting free fatty acid release from adipocytes

Circulating levels of free fatty acids (FFAs) correlate with insulin sensitivity 56, 57. An additional mechanism by which PPAR-γ ligands reverse insulin resistance is by reducing circulating levels of FFAs [58]. This is due to concerted effects on gene expression that lead to an increased net flux of FFAs from the circulation into adipose tissue. The adipogenic function of PPAR-γ ligands increases the number of adipocytes. In mature adipocytes, local generation of FFAs from lipoprotein

PPAR-γ ligand regulation of other adipocyte genes that might contribute to insulin sensitivity

In addition to direct effects on the expression of adipocyte polypeptide hormones and genes that are directly involved in adipocyte FFA metabolism, PPAR-γ ligands regulate the expression of several other genes that enhance glucose metabolism in the adipocyte, including those that encode the insulin-responsive glucose transporter GLUT4 [65] and c-Cbl associating protein (CAP), which is crucial for GLUT4 translocation to the cell surface [66]. Increased glucose uptake into adipocytes directly

Selective PPAR-γ modulators

Because PPAR-γ ligands improve obesity-associated insulin resistance, it is somewhat paradoxical that these drugs also cause weight gain [12], presumably through the combination of increased adipogenesis and fat storage. Other side-effects, notably edema, are likely to result from effects on non-adipose tissue that express PPAR-γ, such as the kidney [69]. However, the possibility that some of these side-effects are PPAR-γ-independent is difficult to exclude. Elimination of adverse effects would

Conclusions and future directions

In addition to their tremendous clinical value, the insulin-sensitizing effects of PPAR-γ ligands have provided a connection between gene regulation by this nuclear receptor and glucose homeostasis. This link could be exploited by development of SPPARMs that retain the insulin-sensitizing properties while avoiding undesirable effects. Additionally, the genes whose regulation mediates the insulin-sensitizing effects of PPAR-γ ligands, such as adipocyte hormones and regulators of FFA metabolism,

Acknowledgements

We thank our colleagues in the Lazar laboratory for stimulating discussions, and the NIDDK, American Diabetes Association, and Bristol Myers Squibb Freedom to Discover Award for support of our laboratory investigations.

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