Serotoninergic Modulation in the Brainstem and Hypothalamus of Female Overnourished Rats: Impact on Mitochondrial markers, Oxidative stress and BDNF mRNA levels

Thyago de Oliveira Rodrigues^1,2Osmar Henrique dos Santos Júnior^1,2Maria Daniele Teixeira Beltrão de Lemos^1,2Matheus Santos De Sousa Fernandes^1,3*Fatma Hilal Yagin^4*Burak Yagin⁴Samarjit Das⁵Abdullah F. Alghannam⁶Pablo Prieto-González⁷Claudia Lagranha^1,2

• ¹Federal University of Pernambuco, Recife, Brazil
• ²Academic Center of Vitoria, Federal University of Pernambuco, Vitória de Santo Antão, Brazil
• ³Keizo Asami Institute, Federal University of Pernambuco, Pernambuco, Brazil
• ⁴Department of Biostatistics and Medical Informatics, Faculty of Medicine, Inonu University, Malatya, Türkiye
• ⁵Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine Baltimore, Baltimore, United States
• ⁶Health Science Research Center, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
• ⁷Sport Sciences and Diagnostics Research Group, GSD-HPE Department, Prince Sultan University, Riyadh 11586, Saudi Arabia, Riyadh, Saudi Arabia

Obesity is a global epidemic identified by the World Health Organization, and its complexity involves genetic, cultural, socioeconomic, and behavioral factors. In this study, we used female Wistar rats, with litters standardized to nine female pups, which were divided into two groups: normally nourished or overnourished. The groups were further subdivided into control and fluoxetine-treated groups, with the pharmacological treatment maintained until the 21st day of life. At 30 days of age, euthanasia was performed, and tissues from the hypothalamus and brainstem were collected. We observed an increase in body weight and the Lee index in the overnourished group, but fluoxetine treatment reduced these indices. Additionally, overnourished rats consumed more palatable food. Biochemically, NADH content in the hypothalamus was altered by overnutrition but restored by fluoxetine treatment. Citrate synthase activity was reduced in the overnourished group in the hypothalamus but increased in the brainstem of fluoxetine-treated rats. The production of reactive oxygen species was higher in the overnourished group, and oxidative stress biomarkers showed increased levels of MDA and protein carbonylation in these rats. Overnutrition impaired the antioxidant activity of enzymes in both the hypothalamus and brainstem, whereas fluoxetine treatment improved this activity. BDNF expression was higher in the fluoxetine-treated groups compared to the overnourished group. These results demonstrate the detrimental effects of maternal overnutrition on the development of female offspring and the therapeutic potential of serotonergic manipulation to mitigate the early effects of obesity, with tissue-specific variations.