Efeitos da ativação do PPAR-β/δ sobre a lipogênese, beta-oxidação e estresse do retículo Endoplasmático hepático num modelo experimental de obesidade

Abstract

The present study aimed to investigate the effects of the treatment with the PPAR-β/δ (Peroxisomal Proliferator Activated Receptor) agonist GW0742 on hepatic energy metabolism and endoplasmic reticulum (ER) stress in diet-induced obese mice. Male C57BL/6 mice (3 months old) received a control diet (C, 10% of lipids, n = 20) or a high-fat diet (HF, 50% of lipids, n = 20) during 10 weeks. These groups were subdivided to receive the treatment (n = 5 per group): C, C-B (PPAR-β/δ agonist, 1.0 mg/kg/day mixed with the control diet), HF and HF-B group (PPAR-β/δ agonist, 1.0 mg/kg/day mixed with the HF diet). The treatment lasted 4 weeks. Were performed biochemical analyzes, western blotting, RT-qPCR, immunofluorescence and transmission electron microscopy (MET). The HF group showed greater body mass (BM) and insulinemia than C, besides an increased hepatic expression of proinflammatory proteins (NF-kB, TNF-α, and IL-6). Conversely, the HF diet reduced the hepatic expression of beta-oxidation related genes (CPT-1a and PPAR-α), while it enhanced the expression of the lipogenic genes (PPAR-γ, FAS, and SREBP-1c). Obese animals showed ER stress, with ultrastructural and molecular alterations, leading to proapoptotic stimulus. The PPAR-β/δ activation by GW0742 rescued the overweight and the insulin resistance, tackled the hepatic inflammation and reduced the lipogenesis concomitant to a favored beta-oxidation. These results complied with the ameliorated ER ultrastructure, reduced ER stress and apoptosis after the treatment. Conclusions: Our results indicate that the PPAR-β/δ activation alleviated the ER stress by improving the insulin sensitivity and maximizing the hepatic energy metabolism with a shift towards beta-oxidation. PPAR-β/δ activation could be an essential tool to avoid the NAFLD (non-alcoholic fatty liver disease) progression and other obesity constraints.