Protective effects of the PPAR β / δ agonist GW0742 on vascular function in obese mice.

M Toral1, M Gomez-Guzman1, M Romero1, R Jimenez1, MP Utrilla2, ME Rodriguez-Cabezas2, J Galvez2, J Duarte0. 1University of Granada, Department of Pharmacology, School of Pharmacy, 18071 Granada, Spain., Spain, 2University of Granada, CIBER-EHD, Department of Pharmacology, School of Pharmacy, 18071 Granada, Spain

Obesity increases the risk of development of metabolic and cardiovascular disease. The abnormalities in adipose tissue function disrupt vascular homeostasis inducing endothelial dysfunction, and a prooxidant and proinflammatory status in the vascular wall (Campia et al., 2012). Administracion of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) agonists to mice fed a high-fat diet (HFD) ameliorated diet-induced obesity and insulin resistance, and effect accompanied by enhanced metabolic rate and fatty acid β-oxidation in skeletal muscles (Tanaka et al., 2003). In non obese spontaneously hypertensive rats the PPARβ/δ agonist GW0742 also improved vascular structure and function independently of systemic metabolic state (Zarzuelo et al., 2011). The aim of the present study was to analyze the effect of chronic GW0742 treatment on vascular function in obese mice fed a HFD.

Male mice were divided into 4 groups (n=10): control, control-treated (GW0742, 3 mg·kg-1·day-1, by oral gavage), HFD, and HFD-treated. Control mice received standard diet, whereas obese mice were fed HFD (60% of its caloric content from fat). Treatment was followed for 12 weeks, and their body weight controlled weekly. One week before sacrificing mice, a glucose tolerance test (GTT) was performed. At the end of treatment, vascular reactivity was assessed using isometric wire myographs, vascular superoxide content by dihydroethidium (DHE) fluorescence, and vascular gene expression by RT-PCR. Statistically analysis for multiple comparisons was carried out by two-way ANOVA analysis followed by Bonferroni post hoc test.

GW0742 administration to mice fed HFD prevented the gain of body weight, as compared to control HFD group (35 ± 4% vs 79 ± 4%, respectively, p<0.01) to values similar to mice fed control diet (27 ± 4%). The increase in the heart weight/tibia length (~29%), kidney weight/tibia length (~8%) and epididimal fat weight/tibia length (~400%) observed in HFD mice as compared to control group were significantly (p<0.01) reduced by GW0742 (~10, 0, and 59%, respectively). The increase in both fasting glucose (~56%) and area under curve in the GTT (~68%) found in HFD group was suppressed by GW0742. Endothelium- and nitric oxide-dependent vasodilatation induced by acetylcholine was decreased in aortic rings from mice fed HFD as compared to control (Maximal effect=31.8 ± 6.0% and 74.0 ± 11.6%, respectively, p<0.01), which was improved by GW0742 (Maximal effect=66.5 ± 6.8%, p<0.01 vs HFD group). No differences among groups were observed in nitroprusside relaxant response. Moreover, GW0742 inhibited (~75%) the increase in ethidium fluorescence found in aortae from HFD group (~2.7 times) as compared to control group. The increased mRNA expression of NOX-1 (~2.2 times) and interleukin-6 (~4.0 times) found in mice fed HFD was abolished by GW0742.

In conclusion, GW0742 prevents obesity, endothelial dysfunction and the vascular pro-oxidant and proinflammatory state in HFD fed mice, showing protective effects of PPARβ/δ activation in early manifestations of atherosclerosis.

Campia U et al., (2012). Br J Pharmacol 165:561-73.

Tanaka T et al., (2003). PNAS 100:15924-9.

Zarzuelo MJ et al., (2011). Hypertension 58:733-43.

Supported by SAF2010-22066 and SAF2008-02616 and Ministerio de Ciencia e Innovación Campus de Excelencia Internacional (Programa GREIB)