EFFECTS OF NEONATAL NUTRITIONAL PROGRAMMING ON THE MESOLIMBIC SYSTEM

• Grant number: 25/15015-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2025
• End date: January 31, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Lucila Leico Kagohara Elias
• Grantee: Beatriz Roxane Antunes Clemente
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 18/18071-5 - Hydroelectrolytic and energy homeostasis: from cellular metabolism to endocrine systems in different phases of development, AP.TEM

Abstract

Obesity is a chronic, multifactorial disease characterized by excess white adipose tissue. It is a serious public health problem associated with several metabolic comorbidities, such as type 2 diabetes, cardiovascular disease, and metabolic syndrome. In addition to genetic and environmental factors, recent studies highlight the role of neonatal nutrition in programming metabolism and eating behavior in adulthood. Energy homeostasis is regulated by hypothalamic pathways, primarily via leptin, a hormone secreted by white adipose tissue, which acts on hypothalamic neurons and is involved in controlling food intake and energy expenditure. In addition to homeostatic control, there is also a hedonic regulation of food intake, mediated by the mesolimbic reward system, particularly by dopaminergic neurons in the ventral tegmental area (VTA), which project to other brain areas such as the nucleus accumbens (NAc).In humans, a critical period of fetal development also involves the establishment of hypothalamic circuits involved in various bodily functions. Thus, changes in maternal nutrition and the maternal metabolic environment impact fetal development and may result in an increased risk of developing metabolic and cardiovascular diseases in juvenile and adult life. For example, intrauterine growth retardation followed by rapid neonatal growth results in altered body composition, cardiovascular disease, insulin resistance, dyslipidemia, diabetes mellitus, liver fat accumulation, and obesity in adulthood.Experimental models have been used to better understand the mechanisms involved in nutritional programming. Nutritional programming can be induced by changes in maternal nutrition in rodents, which can impact the development of plasticity in the hypothalamic and mesolimbic neuronal circuitry. Nutritional changes can be induced by food deprivation, high-fat diets, or sucrose-rich diets. A neonatal nutritional programming model can be implemented by manipulating litter size during lactation, in which pups are maintained in normal litters (NL), large litters (LL), and small litters (SL). In the case of LL litters, there is greater competition for feeding, resulting in neuroendocrine changes in energy homeostasis in adulthood and increased body mass gain.In this context, animal models with neonatal programming, such as those generated in large litters (LL) during lactation, exhibit early malnutrition. However, after weaning, with free diet availability, the animals exhibit hyperphagia, body weight recovery-a form of "catch-up" that can progress to obesity and leptin resistance in adulthood. It is not yet established whether nutritional programming can affect the hedonic component of feeding behavior. This project aims to investigate the effects of neonatal nutritional programming on the dopaminergic circuitry of the VTA, using mice from LL litters compared to animals from control litters. (AU)