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

Mona K Tawfik; Dahlia I Badran; Mohammed M Keshawy; Samy Makary; Mohamed Abdo

doi:10.5114/aoms/158534

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

Arch Med Sci. 2023 Feb 1;19(5):1508-1519. doi: 10.5114/aoms/158534. eCollection 2023.

Authors

Mona K Tawfik¹, Dahlia I Badran^{2

3}, Mohammed M Keshawy⁴, Samy Makary⁵, Mohamed Abdo⁵

Affiliations

¹ Department of Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
² Department of Biochemistry, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
³ Department of Biochemistry, Faculty of Medicine, Badr University, Cairo, Egypt.
⁴ Department of Internal Medicine, Nephrology Division, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
⁵ Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.

Abstract

Introduction: Obesity is one of the most burdensome health problems and is closely linked to leptin resistance. The study examined whether an alternate-day high-fat diet (ADF) and/or GLP-1 agonist (exenatide) modulate brain leptin resistance caused by a high-fat diet (HFD).

Material and methods: 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 a 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.

Results: 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.

Conclusions: In HFD caloric consumption, a combination of ADF and GLP-1 agonist enhances the brain leptin anorexigenic effect with the improvement of the metabolic sequelae of hyperinsulinemia, hyperlipidemia and liver steatosis.

Keywords: alternate-day high-fat diet; exenatide; high-fat diet; hyperinsulinemia; leptin.