Trends in Pharmacological Sciences
Peroxisome proliferator-activated receptor γ in diabetes and metabolism
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.
References (76)
Thiazolidinediones
Endocrinol. Metab. Clin. North Am.
(1997)- et al.
Hepatotoxicity of the thiazolidinediones
Clin. Liver Dis.
(2003) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma)
J. Biol. Chem.
(1995)Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors
Cell
(1992)The organization, promoter analysis, and expression of the human PPARgamma gene
J. Biol. Chem.
(1997)Differential activation of peroxisome proliferator-activated receptors by eicosanoids
J. Biol. Chem.
(1995)A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation
Cell
(1995)15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma
Cell
(1995)Genetic modulation of PPARgamma phosphorylation regulates insulin sensitivity
Dev. Cell
(2003)PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance
Mol. Cell
(1999)
The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance
J. Biol. Chem.
Adipose tissue as an endocrine organ
Trends Endocrinol. Metab.
Resistin and obesity-associated insulin resistance
Trends Endocrinol. Metab.
Inhibition by insulin of resistin gene expression in 3T3-L1 adipocytes
FEBS Lett.
Down-regulation by troglitazone of hepatic tumor necrosis factor-alpha and interleukin-6 mRNA expression in a murine model of non-insulin-dependent diabetes
Biochem. Pharmacol.
Identification of a functional peroxisome proliferator-responsive element in the murine fatty acid transport protein gene
J. Biol. Chem.
Thiazolidinediones block fatty acid release by inducing glyceroneogenesis in fat cells
J. Biol. Chem.
Cloning and characterization of a functional peroxisome proliferator activator receptor-gamma-responsive element in the promoter of the CAP gene
J. Biol. Chem.
Peroxisome proliferator-activated receptor-gamma ligands inhibit adipocyte 11beta -hydroxysteroid dehydrogenase type 1 expression and activity
J. Biol. Chem.
SRC-1 and TIF2 control energy balance between white and brown adipose tissues
Cell
A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity
Mol. Cell
A potent antidiabetic thiazolidinedione with unique peroxisome proliferator-activated receptor gamma-activating properties
J. Biol. Chem.
Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001
J. Am. Med. Assoc.
A war on obesity, not the obese
Science
A clinical view of the obesity problem
Science
Diagnosis, prevention, and intervention for the metabolic syndrome
Am. J. Cardiol.
Economic considerations in treating patients with type 2 diabetes mellitus
Am. J. Health Syst. Pharm.
Type 2 diabetes mellitus in children and youth: a new epidemic
J. Pediatr. Endocrinol. Metab.
Lifetime risk for diabetes mellitus in the United States
J. Am. Med. Assoc.
Rapid increase in the use of oral antidiabetic drugs in the United States, 1990–2001
Diabetes Care
Thiazolidinedione-induced edema
Pharmacotherapy
Thiazolidinediones in diabetes: current status and future outlook
Curr. Opin. Investig. Drugs
Regulation of PPAR gamma gene expression by nutrition and obesity in rodents
J. Clin. Invest.
Differential expression and activation of a family of murine peroxisome proliferator-activated receptors
Proc. Natl. Acad. Sci. U. S. A.
The coregulator exchange in transcriptional functions of nuclear receptors
Genes Dev.
Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: binding and activation correlate with antidiabetic actions in db/db mice
Endocrinology
The structure-activity relationship between peroxisome proliferator-activated receptor gamma agonism and the antihyperglycemic activity of thiazolidinediones
J. Med. Chem.
Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists
Nature
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