PPAR : a dagger in the heart of the metabolic syndrome

Abstract

Obesity is a growing threat to global health by virtue of its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X. The nuclear receptors PPARα and PPARγ are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively, and drugs that modulate these receptors are currently in clinical use. More recent work on the less-described PPAR isotype PPARδ has uncovered a dual benefit for both hypertriglyceridemia and insulin resistance, highlighting the broad potential of PPARδ in the treatment of metabolic disease. PPARδ enhances fatty acid catabolism and energy uncoupling in adipose tissue and muscle, and it suppresses macrophage-derived inflammation. Its combined activities in these and other tissues make it a multifaceted therapeutic target for the metabolic syndrome with the potential to control weight gain, enhance physical endurance, improve insulin sensitivity, and ameliorate atherosclerosis. IntroductionThe prevalence of adult obesity has increased an alarming 75% since 1980, rendering a third of men and women obese in the US (1). This unabated rise has spawned proportionate increases in obesity-associated metabolic disorders, including glucose intolerance, insulin resistance, dyslipidemia, and hypertension, that are well-established risk factors for cardiovascular disease. Known as the metabolic syndrome or syndrome X, this dangerous cluster of pathologies accounts for 6-7% of all-cause mortality and is an expanding health threat. In fact, it is predicted that life expectancy will plateau or decline in the US within the first half of this century because of the magnitude of obesity-associated conditions and the increased rates of obesity in younger populations, particularly children (2, 3). The global obesity problem will require complex solutions, including public health efforts to diminish portion sizes, improve food choices, increase physical activity levels, and raise public awareness. In addition to social and behavioral changes, however, pharmacological interventions to diminish diabetic and cardiovascular complications of the metabolic syndrome are urgently needed.The pathophysiology underlying the metabolic syndrome is incompletely understood, but insulin resistance appears to be an important component (4, 5). Insulin resistance is marked by hyperinsulinemia, enhanced hepatic gluconeogenesis, and impaired insulin-stimulated glucose uptake into skeletal muscle and fat. Elevated levels of circulating FFAs, associated with obesity and insulin resistance, increase fat accumulation in insulin target tissues and contribute to defective insulin action. Indeed, intramuscular fat, based on NMR spectroscopy, correlates strongly with insulin resistance (6). Obese adipose tissue-derived inflammation and altered adipokine secretion may also inhibit insulin signals and affect systemic metabolism (7). The resulting hyperglycemia, dyslipidemia, and hypertension of the metabolic syndrome cause endothelial...

Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells

“…As a nuclear receptor involved in multiple physiological regulations (Cheng et al, 2004;Kim et al, 2004;Piqueras et al, 2007), PPAR-b is an ideal drug target for the treatment of diseases. Studies have shown a wide range of PPAR-b agonists, including eicosanoids, fatty acids and some synthetic compounds (for example, GW501516); GW501516 is currently in a phase II clinical trial for dyslipidemia (Barish et al, 2006;Peraza et al, 2006;Takahashi et al, 2006). Because of its protective role in the carcinogenesis and progression of colon cancer as suggested in this study, PPAR-b may be a potential drug target for colon cancer.…”

Variation in the peroxisome proliferator-activated receptor δ gene in relation to common metabolic traits in 7,495 middle-aged white people

“…In recent years PPARδ has emerged as a key protein in the regulation of energy metabolism by its ability to enhance fatty acid catabolism, energy uncoupling and insulin sensitivity in the liver, adipose tissue and skeletal muscle [6][7][8][9][10]36].…”

Nuclear receptors, mitochondria and lipid metabolism

“…To address these impacts, public health awareness of meal choices and portions, and physical exercise are foremost. However, for those already affected and refractory to diet and exercise changes, pharmacologic modification of metabolism provides an opportunity to prevent mortality and morbidity associated with diabetes, cardiovascular disease and the metabolic syndrome Barish et al 2006).…”

“…Overexpression of VP16-PPARδ in skeletal muscle has profound effects, converting untrained animals into "marathon mice" with a substantial conversion of muscle to a slow-twitch form . While genetic introduction of VP16-PPARδ presents an extreme case, some components of this phenotype are reiterated by ligand treatments and exercise that hint at effective treatments for metabolic syndrome mediated by PPARδ Barish et al 2006). For instance, patients with poor responsiveness to exercise and dietary changes may benefit from a 'jump start' in the form of PPAR agonists.…”