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

To investigate the role of PPAR activation (single PPARα or PPARγ, and dual PPARαγ) on UCP1-dependent and independent thermogenic pathways and mitochondrial metabolism in the subcutaneous white adipose tissue of high-fat-fed mice. Male C57BL/6 mice received either a control diet (C, 10% lipids) or a high-fat diet (HF, 50% lipids) for 12 weeks. Then, the HF group was divided to receive the treatments for four weeks: HFγ (pioglitazone, 10 mg/kg), HFα (WY-14643, 3.5 mg/kg), and HFαγ (tesaglitazar, 4 mg/kg). The HF group was overweight, insulin resistant, and had subcutaneous white adipocyte dysfunction. Treatment with PPARα and PPARαγ 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. PPARα and dual PPARαγ activation recruited UCP1+ beige adipocytes and favored UCP-1 independent 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.