Investigation of the effects of high-fat diet on autophagic, epigenetic and metabolic pathways in mother and pup BALB/c mice, and the potential role of autophagic activation as a treatment tool

Obesity is one of the most important health problems of our age. Factors such as genetics, epigenetics, nutrition and maternal obesity play a role in the development of the obesity. Autophagy is responsible for the destruction of damaged organelles and misfolded proteins, and plays a role in the pathogenesis of the obesity. Many pharmacological agents are used to target the autophagy in the treatment of the obesity. The aim of this study is to determine the effects of high-fat diet and rapamycin which is the autophagy activator in female BALB/c mice. Animals were divided into four groups: Control, Sham, Obese and Obese+Rapamycin (n=10 for each group). Mice in the Obese and Obese+Rapamycin groups were fed with a 60% kcal high-fat diet for 27-29 weeks. After the obesity model was created, 2.5 mg/kg/day rapamycin was administered to mice in the Sham and Obese+Rapamycin groups via oral gavage for 7-9 weeks. During the experiment, the mice were weighed and the average feed consumption during the 4-week treatment period was calculated. In the study, pregnancy was established in all groups after 4 weeks of rapamycin administration and the experiment was terminated on the first day after birth. Obesity occurred in BALB/c mice after the 16th week of the experiment. Rapamycin had no effect on increased body weight, visceral fat mass and index in the obesity; however, it reduced food intake and liver index, but increased the adipocytes' diameter, plasma total cholesterol and HDL levels. Rapamycin also normalized liver weight, fetal macrosomia, plasma TG and ALT levels, but delayed pregnancy and caused fatty liver in the mother and offspring. High-fat diet and rapamycin increased the autophagy at mRNA and protein levels in the maternal liver, decreased it in the offspring liver, and caused an increase in the expression of some genes in the visceral fat. In conclusion, this study demonstrated that rapamycin was partially effective in the treatment of the obesity in female BALB/c mice, and further studies are recommended to determine the effectiveness of this drug in clinical practice.