Alternate-day fat diet and exenatide modulate brain leptin JAK2/STAT3/SOCS3 pathway in fat diet-induced obesity and insulin resistance mouse model

Introduction: Obesity is one of the most burdensome health problems closely linked to leptin resistance. The study examined whether alternate-day high-fat diet (ADF)- and / or GLP-1 agonist (exenatide) modulate brain leptin resistance caused by high-fat diet (HFD).Sixty adult male mice were divided into 6 groups: (i) normal palatable diet (NPD), (ii) exenatide control ( NPD received exenatide) (iii) HFD, (iv) ADF treated, (v) exenatide treated, (vi) ADF and exenatide treated. All animal groups were fed on HFD for 8 weeks, before they received treatment (ADF and/ or Exenatide) for 8 additional weeks. Body weight was assessed at the start and at the end of the experiment, lipid profile, brain leptin and its receptor expression with the leptin-sensitive pathway, JAK2/STAT3/SOCS3/PTP1B, fasting blood glucose (FBG), serum insulin, Liver metabolic handling via its regulators IRS1/PI3K/GLUT4 for hyperinsulinemia/obesity-induced PDK3/NAFLD2 modification, and liver enzymes were determined at the end of the experiment.ADF and exenatide reduced body weight and FBG in HFD-obese mice (p < 0.05). The combined ADF and exenatide regimen enhanced the brain anorexic leptin/JAK2/STAT3 and attenuated the SOCS3/PTP1B pathway (p < 0.05). The ADF/exenatide anorexigenic brain effect also modulated liver glucose via IRS1/PI3K/GLUT4 expression (p < 0.05), attenuating NAFLD2 and PDK3 expression (p < 0.05). Liver enzymes and the histopathological profile confirmed the improvement.In HFD caloric consumption, a combination of ADF and GLP-1 agonist enhances the brain leptin anorexigenic effect with the improvement of the metabolic sequel as hyperinsulinemia, hyperlipidemia and liver steatosis.