Avaliação dos perfis comportamentais e inflamatórios em modelos murinos de obesidade: influência do sexo e do tempo de exposição

Abstract

Advances in the study of the Developmental Origins of Health and Disease (DOHaD) suggest that insults occurring during early developmental stages can trigger significant physiological changes in adulthood, rendering the individual more susceptible to developing conditions such as obesity. In this context, "neonatal overnutrition" is a known factor associated with various metabolic and inflammatory alterations similar to those observed in obesity. It is also known that the persistence of obesity-related inflammatory changes negatively affects neural metabolism and synaptic transmission, leading to behavioral alterations. Thus, this study compared the effects of obesity induced by different murine models on metabolism and behavioral responses in both sexes. Male and female Swiss mice were assigned to control (CTRL) groups or to obesity-induction groups using either litter reduction (SL) or a high-fat diet (HFD). Body mass was monitored weekly after weaning. This monitoring lasted 10 weeks for both experimental groups, extending to 21 weeks for a subgroup of SL animals. Following an acclimatization period, a battery of three behavioral tests (defensive, social interaction, and cognitive) was conducted, followed by an analysis of locomotor activity in an open-field test. To evaluate the influence of time on the progression of the inflammatory response in LR animals, cytokine concentrations and the expression of genes associated with macrophage polarization were analyzed in various tissues at two different time points. Results showed a progressive increase in body mass and adiposity in both models at the 10-week and 21-week marks, with higher food intake observed only in male LR mice. Regarding behavior, female SL mice and both male and female HFD mice exhibited reduced active defense responses. Alterations in social affiliation and social memory were found, and age-dependent cognitive deficits were observed in SL animals of both sexes. Regarding inflammation, male RN mice exhibited an early inflammatory profile—characterized by increased TNF-α concentrations in adipose tissue and the liver, as well as the expression of genes associated with M1 macrophage polarization in the liver—as early as 10 weeks of age. In contrast, female SL mice displayed a delayed and limited inflammatory profile, with increased IL-1β levels observed only in the spleen. These results establish a significant sexual dimorphism by demonstrating that, in both models, obesity manifested as distinct metabolic and behavioral phenotypes in males and females. Furthermore, in SL animals, the progression over time played a significant role in the development of the metabolic and behavioral outcomes observed in both sexes.