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.

Statins are inhibitors of the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In addition to reducing LDL cholesterol, statin treatment increases the levels of the antiatherogenic HDL and its major apolipoprotein apoA-I. Here, we investigated the molecular mechanisms of apoA-I regulation by statins. Treatment with statins increased apoA-I mRNA levels in human HepG2 hepatoma cells, and this effect was reversed by the addition of mevalonate, implicating HMG-CoA reductase as the relevant target of these drugs. Pretreatment with Actinomycin D abolished the increase of apoA-I mRNA, indicating that statins act at the transcriptional level. Indeed, statins increased the human apoA-I promoter activity in transfected cells, and we have identified a statin response element that coincides with a PPARα response element known to confer fibrate responsiveness to this gene. The statin effect could be abolished not only by mevalonate, but also by geranylgeranyl pyrophosphate, whereas inhibition of geranylgeranyl transferase activity or treatment with an inhibitor of the Rho GTP-binding protein family increased PPARα activity. Using dominant negative forms of these proteins, we found that Rho A itself mediates this response. Because cotreatment with statins and fibrates activated PPARα in a synergistic manner, these observations provide a molecular basis for combination treatment with statins and fibrates in coronary heart disease.

Our data demonstrate that CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and induced by PPAR activation, identifying a potential role for PPARs in cholesterol homeostasis in atherosclerotic lesion macrophages.

Peroxisome proliferator-activated receptor (PPAR)-␣ controls the expression of genes involved in lipid metabolism. PPAR-␣ furthermore participates to maintain blood glucose during acute metabolic stress, as shown in PPAR-␣-null mice, which develop severe hypoglycemia when fasted. Here, we assessed a potential role for PPAR-␣ in glucose homeostasis in response to long-term high-fat feeding. When subjected to this nutritional challenge, PPAR-␣-null mice remained normoglycemic and normoinsulinemic, whereas wild-type mice became hyperinsulinemic (190%; P < 0.05) and slightly hyperglycemic (120%; NS). Insulin tolerance tests (ITTs) and glucose tolerance tests (GTTs) were performed to evaluate insulin resistance (IR). Under standard diet, the response to both tests was similar in wild-type and PPAR-␣-null mice. Under high-fat diet, however, the efficiency of insulin in ITT was reduced and the amount of hyperglycemia in GTT was increased only in wild-type and not in PPAR-␣-null mice. The IR index, calculated as the product of the areas under glucose and insulin curves in GTT, increased fourfold in high-fat-fed wildtype mice, whereas it remained unchanged in PPAR-␣-null mice. In contrast, PPAR-␣ deficiency allowed the twofold rise in adiposity and blood leptin levels elicited by the diet. Thus, the absence of PPAR-␣ dissociates IR from high-fat diet-induced increase in adiposity. The effects of PPAR-␣ deficiency on glucose homeostasis seem not to occur via the pancreas, because glucosestimulated insulin secretion of islets was not influenced by the PPAR-␣ genotype. These data suggest that PPAR-␣ plays a role for the development of IR in response to a Western-type high-fat diet. Diabetes 50: 2809 -2814, 2001 M itochondrial ␤-oxidation is the major metabolic process by which fatty acids are utilized intracellularly, thus providing energy primarily for the heart and skeletal muscles. In the liver, ␤-oxidation also provides the substrates required for the synthesis of ketone bodies and supplies ATP and reducing equivalents to sustain gluconeogenesis. The physiological impact of enzymatic defects in these pathways is evidenced by the phenotype of patients with inherited ␤-oxidation deficiency. The clinical presentation includes cardiomyopathy, liver and muscle dysfunction, and episodes of nonketotic hypoglycemia (rev. in Eaton et al. [1]). Recently, a mouse model of ␤-oxidation deficiency was produced by targeted disruption of long-chain acylCoA dehydrogenase, an enzyme that catalyzes the initial step of this pathway. These mice display several features that resemble those of patients with ␤-oxidation defects, including reduced tolerance to fasting as a result of hypoglycemia and hepatic and cardiac disturbances (2).The peroxisome proliferator-activated receptor (PPAR)-␣ plays a central role in the control of mitochondrial ␤-oxidation of fatty acids. PPAR-␣-null mice (3) exhibit a reduced capacity to metabolize long-chain fatty acids (4,5), which likely contributes to dyslipidemia (6) and larger adipose stores observed in th...