Modulatory effect of PPAR-γ by acetate on cardiorenometabolic disturbance associated with high fat diet–fed insulin-resistant male Wistar rats

Insulin resistance (IR) is a critical pathogenic factor for cardiovascular disease (CVD) and chronic kidney disease (CKD). These two diseases represent the most prominent cause of death and morbidity globally. Short chain fatty acids, particularly acetate elicits cardioprotective effects. Herein, we investigated the effects of acetate on IR-driven cardiorenal disorder and the likely involvement of peroxisome proliferator-activated receptor-γ (PPAR- γ) in rats exposed to high-fat diet (HFD). Ten-week-old male Wistar rats were assigned into three groups (each group is n = 6): The groups received distilled water as vehicle (po), 40% HFD and 40% HFD plus 200 mg/kg sodium acetate (po) respectively for 12 weeks. HFD induced IR accompanied with glucose tolerance dysfunction and an enlarged cardiac mass while retaining the renal mass. Besides, HFD increased cardiac/renal lipid indices and low-density lipoprotein, malondialdehyde, γ-glutamyl transferase, uric acid and histone deacetylase-2 (HDAC2) level as well as reduced glutathione, PPAR-γ and nitric oxide concentration. It also increased plasma urea, creatinine, troponin T and creatinine kinase and increased cardiac but not renal lactate and lactate dehydrogenase. The Immunohistochemical examination of cardiac and renal tissues revealed presentation of severe expression of inflammasome in the HFD group in comparison with the control group. Nevertheless, supplementation with acetate ameliorated these changes. The present results demonstrate cardiorenometabolic disturbance in HFD-induced IR which coexist with a deficiency of PPAR-γ. The results suggest that acetate, which is an HDAC inhibitor, ameliorates cardiorenometabolic perturbations by increasing PPAR-γ and insulin sensitivity with attenuation of oxidative and pro-inflammation.