Estudo do potencial efeito terapêutico da metformina durante adolescência sobre as disfunções metabólicas observadas em ratos adultos amamentados por mães obesas

Abstract

Considered one of the main metabolic dysfunctions, often associated with physiological insults occurring in early life (intrauterine, lactation and adolescence), obesity is one of the main health problems worldwide. The nutrition of offspring in early life is crucial for healthy development, a fact that, depending on the maternal nutritional quality, can lead to the development of metabolic diseases in later life. In this regard, metformin is an important drug in the treatment of obesity. This study aimed to evaluate the role of metformin treatment, only during adolescence, as a possible deprogrammer of metabolic dysfunctions induced by maternal obesity during lactation, analyzing the sex-dependent effect of both maternal obesity and metformin in the offspring. During lactation, Wistar rats nursing 8 pups (4 males and 4 females) were fed a hypercaloric diet (4,589 kcal) plus 10% sucrose solution (Obese group), while control rats fed a rodent chow (Cont group). Maternal weight and intake, as well as milk composition, body composition and biochemical parameters were assessed. During lactation, weight gain and milk intake of the offspring were evaluated. From 30 to 60 days-old, half of the offspring were treated with metformin (250 mg/kg in drinking water; Cont-Met and ObMet groups), while the other half drank only water (Cont and Ob groups). The rats were subjected to glucose intolerance (ipGTT) and insulin (ipITT) tests, and at 120 days-old they were euthanized for tissue collection (lean mass and fat mass) and blood for later evaluation of body composition, lipid profile and liver function. Compared to the Cont group, Obese group consumed more calories and, at the end of lactation, showed an increase in body weight, liver weight and adiposity (P<0.05), as well as an increase in triglycerides, TyG index, AST, ALT and oxidative stress markers (TBARS, carbonyl and hepatic CAT), associated with reduced HDL cholesterol (P<0.05). The milk of Obese rats was more caloric compared to that of the Cont group (P<0.01). The offspring of Obese mothers (males and females) consumed more milk than the Cont offspring and showed greater weight gain (P<0.01), which was earlier in males. The weight gain of Ob-Met rats, during and after treatment with metformin, was reduced by 10%, compared to Cont (P<0.05). Male Ob pups showed increase in total cholesterol, triglycerides, glucose, AST and ALT, while Ob-Met rats showed reduction in these parameters. Female Ob rats showed increase in triglycerides and VLDL cholesterol, while Ob-Met rats showed reduction. Ob-Met rats presented hypoglycemia compared to Ob rats, which did not occur in males. In conclusion, lactating rats fed a hypercaloric diet develop obesity associated with liver dysfunction and more caloric milk, therefore their pups, especially males, consume more milk and gain body weight earlier, developing obesity and metabolic dysfunction as longterm consequence. Metformin reduces weight gain and improves biochemical parameters, showing efficacy in reducing metabolic risks associated with maternal obesity.