Avaliação do metabolismo hepático em ratos Wistar adultos de ambos os sexos em modelos de programação no período da lactação: papel da exposição materna à nicotina, do desmame precoce e da restrição proteica materna

Abstract

Experimental studies show that protein restriction, early weaning and maternal exposure to nicotine during lactation are factors that promote endocrine-metabolic alterations in adult male offspring, increasing the risk for liver dysfunction. In our research group, we observed that Wistar rats programmed to overweight and obesity in adulthood, by experimental models of early weaning and maternal exposure to nicotine, have impaired liver function, with the presence of microvesicular steatosis and redox imbalance. On the other hand, offspring programmed for low weight by maternal protein restriction have unchanged liver mass and architecture. However, due to metabolic changes previously described, it is possible that the maintenance pathways of glycemic and lipid homeostasis in the liver are functioning in an altered way in order to supply the body's needs. Thus, to investigate the molecular pathways involved in liver phenotypes in these three programming models exclusively caused by imprinting during lactation, in this Thesis we analyze the main enzymes and transcription factors related to the pathways of liver glycemic and lipid metabolism (gluconeogenesis, lipogenesis, β-oxidation and VLDL assembly), histology as well as the liver response to intraperitoneal administration of gluconeogenic substrate. The adult female offspring was studied for the first time by our group, considering the possibility of distinct responses associated with gender. Programming model by nicotine exposure: Two days after birth, minipumps were implanted in lactating rats, which were divided into Nicotine group (6 mg/kg/day for 14 days) and Control group (saline solution for 14 days). Males showed alterations in triglyceride metabolism, preferentially with intrahepatic accumulation, independently of overweight and insulin resistance. Conversely, the accumulation of lipids in females occurred preferentially in the plasma and the hepatocyte architecture was preserved, with alterations mainly in the cholesterol metabolism. Programming model by early weaning: Lactating rats were divided into: 1) non-pharmacological EW group: wrapped with an adhesive bandage in the last 3 days of lactation; 2) Pharmacological EW: received bromocriptine (1mg/kg BW/day) in the last 3 days of lactation; and 3) Control: whose pups were weaned at 21 days. Only males from the non-pharmacological EW showed alterations in the liver cytoarchitecture associated with differences in the Fatty Acid Sintase (FAS) and Stearoil-CoA Desaturase-1 (SCD-1) protein expression. Females, regardless of the type of weaning, did not develop liver steatosis, although they have a higher content of the enzyme related to the export of hepatic triglycerides, which may influence the best lipid profile observed. Programming model by low-protein diet: Throughout lactation period, lactating dams received a standard diet (23% protein) or a low-protein diet (8% protein). Maternal protein restriction during lactation does not program the accumulation of hepatic lipids in the adult offspring, although several repair pathways for homeostasis have been altered in males and females, possibly compromising the maintenance of liver function