PPAR-αe PPAR-β/δ: Efeitos singulares sobre a plasticidade do tecido adiposo branco-marrom e potencialização da termogênese no tecido adiposo marrom de camundongos obesos

Abstract

Obesity as a complex nosological entity stimulates the search for treatments to heal its metabolic alterations. Peroxisome proliferator-activated receptors (PPARs) are essential transcription factors for adipogenesis and adipocyte plasticity, but the isolated role of alpha and beta isoforms in the browning phenomenon and changes in thermogenically active brown adipose tissue (BAT) is not yet described. The present study aimed to evaluate the effects of PPAR-α or PPAR-β/δ activation on the induction of beige cells in the subcutaneous white adipose tissue (WATs) and thermogenic pathway of BAT in C57BL/6 mice fed a high-fat diet. All procedures were approved by the Ethics Committee for the Care and Use of Experimental Animals of IBRAG (CEUA, protocol No. 034/2016). Sixty animals were randomly allocated to the control group (C, diet based on AIN-93M for rodents, with 10% of the energy derived from lipids) or in the hyperlipid group (HF, diet based on AIN-93M for rodents, with 50% energy derived from lipids) for 10 weeks. Each group was then redivided for the initiation of the four-week treatment, totaling six groups (n = 10, each): C, C-alpha (C plus PPAR-alpha agonist C, 2.5 mg / kg body mass-BM ), C-beta (C plus PPAR-beta agonist, 1 mg / kg BM), HF, HF-alpha (HF plus PPAR-alpha agonist), and HF-beta (HF plus PPAR-beta agonist).Agonists were added to the respective diets. HF animals were overweight, oral glucose intolerance and had adipocyte hypertrophy. Both treatments reversed these parameters. The browning phenomenon, verified by the presence of multilocular beige cells positive for UCP1 and increased body temperature, was only observed in the groups treated with PPAR-alpha agonist. Activation of PPAR-alpha also promoted a significant increase in the expression of the selective gene for the beige adipocyte TMEM26, the effector gene of thermogenesis UCP1 and PRDM16, essential for the maintenance of the beige phenotype. Increased gene expression of CIDEA concomitant with the reduction of UCP1 gene and protein expression in animals treated with PPAR-beta may justify the predominance of the white phenotype in its adipocytes, although with a significant reduction in the mean sectional area of ​​these cells, treatment with PPAR-α was also able to increase energy expenditure.he PPAR-α agonist also increased the gene expression of PPAR-α, PGC1-α, PRDM16, β3-AR, BMP-8b, PDK4 and TFAM in TAM. This work shows that treatment with PPAR-beta agonist relieved metabolic disorders by increasing beta-oxidation and improved glucose tolerance, while the PPAR-alpha agonist was confirmed as a promising therapeutic target for treating metabolic diseases from induction of beige adipocytes and increased thermogenesis.