Peroxisome Proliferator-activated Receptor α Activators Improve Insulin Sensitivity and Reduce Adiposity

Abstract

Fibrates and glitazones are two classes of drugs currently used in the treatment of dyslipidemia and insulin resistance (IR), respectively. Whereas glitazones are insulin sensitizers acting via activation of the peroxisome proliferator-activated receptor (PPAR) ␥ subtype, fibrates exert their lipid-lowering activity via PPAR␣. To determine whether PPAR␣ activators also improve insulin sensitivity, we measured the capacity of three PPAR␣-selective agonists, fenofibrate, ciprofibrate, and the new compound GW9578, in two rodent models of high fat diet-induced (C57BL/6 mice) or genetic (obese Zucker rats) IR. At doses yielding serum concentrations shown to activate selectively PPAR␣, these compounds markedly lowered hyperinsulinemia and, when present, hyperglycemia in both animal models. This effect relied on the improvement of insulin action on glucose utilization, as indicated by a lower insulin peak in response to intraperitoneal glucose in ciprofibrate-treated IR obese Zucker rats. In addition, fenofibrate treatment prevented high fat diet-induced increase of body weight and adipose tissue mass without influencing caloric intake. The specificity for PPAR␣ activation in vivo was demonstrated by marked alterations in the expression of PPAR␣ target genes, whereas PPAR␥ target gene mRNA levels did not change in treated animals. These results indicate that compounds with a selective PPAR␣ activation profile reduce insulin resistance without having adverse effects on body weight and adipose tissue mass in animal models of IR. MS,1 which develops as a result of IR (1), is characterized by glucose intolerance, hyperinsulinemia, dyslipidemia, and hypertension. These metabolic abnormalities are frequently associated with visceral obesity (2). The clustering of multiple cardiovascular risk factors in MS results in increased risk for atherosclerotic vascular disease, the major cause of mortality and morbidity in type 2 diabetic patients (3). Pharmacological treatment of MS should therefore aim at ameliorating IR and reducing cardiovascular risk factors.

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

“…Studies in animals indicate that PPAR-α agonists increase hepatic fat oxidation and reduce hepatic fat content in association with enhanced insulin-mediated suppression of EGP [3,7,43,48]. Although hepatic fat oxidation was not measured in the present study, we did not observe a significant reduction in hepatic fat content or an increase in hepatic insulin sensitivity (in contrast to PIO therapy) following FENO therapy.…”

“…Studies in rodents conclusively demonstrate that PPAR-α activation with FENO and other more potent PPAR-α agents enhances peripheral (muscle) and hepatic insulin sensitivity [4][5][6][7][8]. Although PPAR-α-null mice do not manifest any obvious alteration in insulin sensitivity [42], PPAR-α activation in nutritional (high-fat diet), genetic (Zucker obese fa/fa rat), and lipoatrophic (A-ZIP/ F-1) models of insulin resistance markedly improves insulin sensitivity [4,7,43] and reduces visceral fat in the two former models. Intracellular fatty acids and their derivatives interfere with insulin-stimulated glucose metabolism, through an effect on the insulin-signalling pathway, possibly by activating protein kinase C [1,44].…”

“…FENO and gemfibrozil) for the treatment of hypertriacylglycerolaemia in type 2 diabetic patients, their effect on insulin sensitivity in humans has not been rigorously examined and conflicting results have been reported [9][10][11][12][13][14]. Studies in rodents conclusively demonstrate that PPAR-α activation with FENO and other more potent PPAR-α agents enhances peripheral (muscle) and hepatic insulin sensitivity [4][5][6][7][8]. Although PPAR-α-null mice do not manifest any obvious alteration in insulin sensitivity [42], PPAR-α activation in nutritional (high-fat diet), genetic (Zucker obese fa/fa rat), and lipoatrophic (A-ZIP/ F-1) models of insulin resistance markedly improves insulin sensitivity [4,7,43] and reduces visceral fat in the two former models.…”

“…Intracellular fatty acids and their derivatives interfere with insulin-stimulated glucose metabolism, through an effect on the insulin-signalling pathway, possibly by activating protein kinase C [1,44]. In rodents it has been suggested that PPAR-α activation increases fatty acid oxidation, thus decreasing intramyocellular lipid content and improving insulin sensitivity [4][5][6][7]. In contrast, PPAR-α-null mice are protected from high-fat diet-induced insulin resistance [42].…”

“…PPAR-α agonists have been used to treat hypertriacylglycerolaemia and reduce cardiovascular risk [2,3]. Studies in rodents clearly demonstrate that PPAR-α agonists improve hepatic and muscle insulin resistance, decrease hepatic and intramuscular fat content, reduce plasma NEFA and enhance adiponectin (AD) expression [4][5][6][7][8]. Some [9][10][11], but not all [12][13][14], studies in humans with hypertriacylglycerolaemia and/or type 2 diabetes suggest that PPAR-α agonists, i.e.…”