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

By M. Guerre-Millo, P. Gervois, E. Raspé, L. Madsen, P. Poulain, B. Derudas, J. Herbert, D. Winegar, T. Willson, J. Fruchart and 2 more. Journal of Biological Chemistry, 2000

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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) γ subtype, fibrates exert their lipid-lowering activity via PPARα. To determine whether PPARα activators also improve insulin sensitivity, we measured the capacity of three PPARα-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 PPARα, 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 PPARα activationin vivo was demonstrated by marked alterations in the expression of PPARα target genes, whereas PPARγ target gene mRNA levels did not change in treated animals. These results indicate that compounds with a selective PPARα activation profile reduce insulin resistance without having adverse effects on body weight and adipose tissue mass in animal models of IR.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/c3c8dfcf76b25a3d344f9387d72db090f237bb62

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Citations in the corpus

New drug targets for type 2 diabetes and the metabolic syndrome (2001, background): “, and recent observations suggesting an independent insulin-sensitizing effect of PPARα agonist”
The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. (2004, background): “In PPAR- –null mice, there is no gross alteration of insulin sensitivity (23).”
PPARs and the complex journey to obesity (2004, background): “In a variety of mouse models, PPAR-α agonists lower plasma triglycerides, reduce adiposity and improve hepatic and muscle steatosis, consequently improving insulin sensitivit”
Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. (2015, background): “In contrast to the observation that PPARa activation improves insulin sensitivity [129], Ppara-deficient mice are protected from HFD-induced IR, as assessed by glucose tolerance test and euglycemic-hyperinsulinemic clamps in fasted mice [129,130].”
Integrated physiology and systems biology of PPARα (2014, neutral): “[95] Guerre-Millo, M.”
International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors (2006, background): “Increased fatty acid oxidation by activated PPAR (cid:1) lowers circulating tri-glyceride levels, liver and muscle steatosis, and reduces adiposity, which improves insulin sensitivity (Guerre-Millo et al., 2000; Chou et al., 2002; Kim et al., 2003).”