Efeitos do tratamento com Tesaglitazar, Pioglitazona e WY-14643 no eixo intestino-adiposo em camundongos alimentados com dieta hiperlipídica

Abstract

Objective: To evaluate the role of tesaglitazar (agonist PPARα/γ), pioglitazone (agonist PPARγ), and WY-14643 (agonist PPARα) in controlling endotoxemia, white adipose tissue browning, and whitening of brown adipose tissue in mice fed excess saturated fat. Methods: Male C57BL/6 mice received a control diet (C, 10% lipids) or high-fat diet (HF, 50% lipids) for 12 weeks. Then, the HF group was divided to receive treatments for four weeks: HFγ (pioglitazone, 10 mg/kg), HFα (WY-14643, 3.5 mg/kg), and HFαγ (tesaglitazar, 4 mg/kg). Results: The HF group presented excess weight, oral glucose intolerance, intestinal dysbiosis, altered intestinal permeability, and endotoxemia, culminating in the whitening of the interscapular brown adipose tissue (iBAT). Downregulation of LPS-Tlr4 signaling supported the reduction of inflammation and improved lipid metabolism in iBAT in the HFαγ group, the only one to show normalized body mass (BM) and increased energy expenditure. Tesaglitazar also mitigated insulin resistance and induced subcutaneous white adipose tissue (sWAT) browning with increased activation of UCP1-dependent and -independent thermogenesis, with improved mitochondrial metabolism to support the beige adipocyte phenotype. Conclusion: PPARα/γ synergism treated obesity, improving the intestine-adipose tissue axis, where the restored intestinal microbiota and reestablished intestinal permeability controlled endotoxemia and reversed iBAT whitening and promoted WATs browning through favored thermogenesis, producing normalization of BM and insulin sensitivity. The results place PPARα/γ synergism as a potential target for obesity treatment, with possible clinical applications.