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Peroxisome proliferator–activated receptor γ ligands and atherosclerosis: ending the heartache
| Content Provider | Semantic Scholar |
|---|---|
| Author | Rosen, Evan D. Spiegelman, Bruce M. |
| Copyright Year | 2000 |
| Abstract | One of the great ironies of the present-day industrialized world is serious disease and death brought about by too much rich food and too little physical exertion. The incidence of obesity has increased to the point that one in two American adults is now considered overweight (1). Pathologies linked to obesity, such as type 2 diabetes, hypertension, and cardiovascular disorders, are also increasingly prevalent in our society. The tight linkage of obesity, insulin resistance (and frank diabetes), dyslipidemia, and hypertension has been widely observed and has been dignified with a label – syndrome X, or the metabolic syndrome (2). The exact pathogenic relationships between the component conditions of the metabolic syndrome are complex and incompletely understood, despite significant and ongoing efforts to identify susceptibility genes in human populations and animal models. The convergence of these conditions in the metabolic syndrome is not an area isolated to mere academic interest: Coronary and peripheral vascular disease leading to myocardial infarction and stroke is the unhappy fate of many affected individuals. In an ideal world, the metabolic syndrome would be treated by diet and exercise, leading to weight loss. Even relatively modest degrees of weight loss have been shown to improve markers of the metabolic syndrome, such as blood pressure, serum cholesterol, and insulin levels. Unfortunately, most patients find the necessary dietary and exercise regimens to be difficult. Even if the difficulty is surmounted, they find that their bodies resist any deviation from the “set-point” of their elevated weight. Much emphasis, therefore, has been placed on treating the component conditions of the metabolic syndrome pharmacologically. Indeed, these efforts have been successful, and new medications for hypertension and dyslipidemia are now available that can reduce morbidity and mortality from cardiovascular disease in these patients. The treatment of insulin resistance and diabetes has until recently been restricted to the administration of exogenous insulin or to sulfonylureas, which promote the release of endogenous insulin. Although effective at reducing serum glucose levels in diabetic patients, neither of these agents addresses the underlying insulin resistance at the core of the metabolic syndrome. In the last five years, however, metformin became available in the US. Metformin reduces insulin resistance primarily in the liver, although its precise molecular targets are not known. Unfortunately, the use of metformin in patients with significant renal, hepatic, or cardiac impairment can lead to life-threatening lactic acidosis, reducing the utility of this agent in many people with diabetes (3). It was with considerable excitement, therefore, that the thiazolidinedione (TZD) drugs were introduced into the US market in the last five years. Like metformin, these antidiabetic agents, such as troglitazone (Rezulin™), rosiglitazone (Avandia™), and pioglitazone (Actos™), were originally developed without knowledge of their mechanism of action. Several lines of evidence, however, have now converged to identify the peroxisome proliferator–activated receptor γ (PPARγ) as the relevant molecular target of these compounds (4). Perhaps most convincing is the fact that non-TZD synthetic compounds isolated solely on the basis of binding to PPARγ, a ligand-activated transcriptional regulator, exert antidiabetic effects similar to those of the TZDs (5). As discussed by Olefsky (6) and others in the recent JCI Perspective series on insulin resistance, TZDs reduce insulin resistance and improve glucose homeostasis in diabetic rodents and humans. Nevertheless, concerns remain about possible deleterious side effects of these drugs. Troglitazone, the first TZD approved, was shown to have hepatotoxic effects in some patients during postmarketing analysis (7). Unfortunately, this reaction was severe enough in a few patients to cause death or a requirement for liver transplantation, leading to the withdrawal of this drug from the US market. Thus far, monitoring of patients taking rosiglitazone and pioglitazone has not revealed significant hepatotoxicity suggesting that this undesired effect may be idiosyncratic to troglitazone and not related to the activation of PPARγ per se. A more precise understanding of the spectrum of side effects of rosiglitazone and pioglitazone must await more studies in larger numbers of patients. One complicating feature in the use of PPARγ agonists is that the precise tissue targets relevant to metabolic disease are not fully understood. PPARγ is expressed at its highest levels in adipose tissue, with lower levels expressed in many cell types, including monocytes, skeletal muscle, vascular endothelial cells, and breast, colon, and prostate epithelium. PPARγ is a dominant regulator of many aspects of fat cell biology, including adipose cell differentiation, fatty acid uptake, and lipogenesis, raising the possibility that the insulin-sensitizing effects of TZDs reflect the increased performance of TZD-treated adipose tissue as a sink for both fat and glucose. On the other hand, it is entirely possible that TZDs act primarily through PPARγ in other tissues such as muscle, liver, or the β cells of the pancreas. Global deletion of the PPARγ gene in mice results in placental dysfunction and embryonic lethality (8, 9), so resolution of this question in a definitive way will require the construction of tissue-specific knockouts. |
| Starting Page | 629 |
| Ending Page | 631 |
| Page Count | 3 |
| File Format | PDF HTM / HTML |
| DOI | 10.1172/JCI10909 |
| Alternate Webpage(s) | http://dm5migu4zj3pb.cloudfront.net/manuscripts/10000/10909/JCI0010909.pdf |
| Alternate Webpage(s) | https://doi.org/10.1172/JCI10909 |
| Volume Number | 106 |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
