Peroxisome proliferator-activated receptors-alpha and gamma synergism modulate the gut-adipose tissue axis and mitigate obesity

To evaluate the effects of single PPARα or PPARγ activation, and their synergism (combined PPARα/γ activation) upon the gut-adipose tissue axis, focusing on the endotoxemia and upstream interscapular brown adipose tissue (iBAT) function in high-saturated fat-fed mice. Methods: Male C57BL/6 mice received 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 HFα/γ (tesaglitazar, 4 mg/kg). Results: The HF group exhibited overweight, oral glucose intolerance, gut dysbiosis, altered gut permeability, and endotoxemia, culminating in iBAT whitening. The downregulation of LPS-Tlr4 signaling underpinned reduced inflammation and improved lipid metabolism in iBAT in the HFα/γ group, the unique to show normalized body mass and increased energy expenditure. Conclusion: PPARα/γ synergism treated obesity by ameliorating the gut-adipose tissue axis, where restored gut microbiota and permeability controlled endotoxemia and rescued iBAT whitening through favored thermogenesis. •Obesity impairs the gut-adipose axis, collaborating with brown adipose tissue whitening.•PPARα, PPARγ and PPARα/γ synergism alleviated gut dysbiosis and endotoxemia.•PPARα/γ agonist improved gut ultrastructure and brown adipocyte batokines (Vegfa and Bmp8b).•Only PPARα/γ synergism increased thermogenesis and energy expenditure, rescuing obesity.•Only PPARα/γ synergism coupled rescued dysbiosis with whitening alleviation in mice.