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

Abstract

IntroductionIntroduction: 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).Material and methodsSixty 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.ResultsADF 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.ConclusionsIn 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.

Evidence That Peripheral Leptin Resistance in Omental Adipose Tissue and Liver Correlates with MASLD in Humans

“…Our data align with the differences between MASLD and MASH biopsies in the presence of SOCS3 [130], as well as with studies showing that SOCS3 inhibition prevents M1 polarization of Kupffer cells and steatotic progression to inflammation [131]. This demonstrates that comparable events occur in the liver and CNS [132,133].…”

Fasting Protocols Do Not Improve Intestinal Architecture and Immune Parameters in C57BL/6 Male Mice Fed a High Fat Diet

“…The effects of TRF and ADF on metabolic dysfunction and weight loss have been extensively studied in both animals and humans. In mice fed a high fat diet (HFD), TRF and ADF increased weight loss, decreased fat mass, and prevented adiposity, as well as improved glucose tolerance, insulin-and leptin resistance, and LDL cholesterol and triacylglycerol concentrations [ 2 , 4 ]. Similar results have also been observed in humans [ 3 , 5 ].…”

The year in nutrition medicine 2023

“…Overall, the Western world – but also most developing countries – eats too much energy. This is progressively increasing the scientist attention towards low-energy diets and different form of fasting as therapeutic and preventive tools [ 3 , 4 ].…”