PPAR/ synergism activates UCP1-dependent and-independent thermogenesis and improves mitochondrial dynamics in the beige adipocytes of high-fat fed mice

Objective: The aim of this study was to investigate the role of peroxisome proliferator-activated receptor (PPAR) activation (single PPARa or PPARy, and dual PPARa/y) on UCP1-dependent and-independent thermogenic pathways and mitochondrial metabolism in the subcutaneous white adipose tissue of mice fed a high-fat diet. Methods: Male C57BL/6 mice received either a control diet (10% lipids) or a high-fat diet (HF; 50% lipids) for 12 wk. The HF group was divided to receive the treatments for 4 wk: HFy (pioglitazone, 10 mg/kg), HFa (WY-14643, 3.5 mg/kg), and HFa/y (tesaglitazar, 4 mg/kg).Results: The HF group was overweight, insulin resistant, and had subcutaneous white adipocyte dysfunction. Treatment with PPARa and PPARa/y reduced body mass, mitigated insulin resistance, and induced browning with increased UCP1-dependent and-independent thermogenesis activation and improved mitochondrial metabolism to support the beige adipocyte phenotype.Conclusion: PPARa and dual PPARa/y activation recruited UCP1+ beige adipocytes and favored UCP1-inde-pendent thermogenesis, yielding body mass and insulin sensitivity normalization. Preserved mitochondrial metabolism emerges as a potential target for obesity treatment using PPAR agonists, with possible clinical applications.(c) 2023 Elsevier Inc. All rights reserved.