Saroglitazar, a novel dual PPAR-alpha/gamma agonist, reverses high fat-low protein diet-induced metabolic and cognitive aberrations in C57BL/6J male mice

Aims: Insulin resistance (IR) has become one of the major causative factors for the pathogenesis of various metabolic and neurometabolic diseases. The sedentary lifestyle in association with the consumption of protein-deficient and high-calorie diet results in IR development. This study was aimed to evaluate the neuroprotective effects of Saroglitazar (SGZ), a dual peroxisome-pmliferator activated receptor (PPAR-alpha/gamma) in a high fat-low protein diet (HFLPD) fed mouse model of MetS and associated cognitive deficits. Methods: Adult male C57BL/6J mice were fed with HFLPD plus 15% oral fructose solution for 16 weeks. Starting at the 13th week, SGZ (5 & 10 mg/kg; p. o.) was administered along with HFLPD for four weeks, i.e., the 12th to 16th week of the study groups. Various physiological, serum metabolic, neurobehavioral, neuroinflammatory, and oxidative stress parameters were assessed. The brain histopathology and mRNA expression of diverse genes in specific brain regions were also estimated. Results: The treatment with SGZ at both doses have significantly reversed various HFLPD-induced metabolic and cognitive alterations by improving the glucose and lipid profile in the periphery in addition to the enhanced cerebral glucose homeostasis, BBB integrity, reduced oxidative stress, and neuroinflammation. Furthermore, the SGZ improved locomotion and memory retention while reducing the HFLPD-induced anxiety-like behaviors in the mice. Conclusions: SGZ treatment showed significant metabo-neuroprotective effects in mice fed with HFLPD, possibly through peripherally mediated activation of PPAR-alpha/gamma and insulin downstream signaling in the cortex and hippocampus.