Role of AgRP and POMC neurons and mesolimbic pathways on the control of food intake in neonatal nutritional programming

• Grant number: 24/22147-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: March 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: Henrique Rodrigues Vieira
• 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

The prevalence of global obesity has increased significantly in recent decades at different age. Obesity is characterized by the presence of excess body adiposity and comprises a risk factor for coronary disease and metabolic syndrome. Nutritional changes that occur during developmental period can affect energy homeostasis in adult life. Prenatal and neonatal programming has been related to epigenetic changes, which culminate in changes in the expression of genes involved with control of energy homeostasis. It is already well established that the hypothalamus plays an important role in energy homeostasis, as well as in hedonic components of food intake. The arcuate nucleus of the hypothalamus plays an essential role in energy homeostasis by integrating hormonal signals released by the gastrointestinal tract and adipose tissue, such as leptin, insulin, and ghrelin, which in turn can activate or inhibit neurons that express anorexigenic and orexigenic neuropeptides, such as POMC and AgRP, respectively. Furthermore, it has been demonstrated that leptin also participates in the hedonic component of food intake, acting on neurons in the lateral hypothalamic area, expressing neurotensin and galanin, which in turn inhibit orexinergic neurons and send projections to mesolimbic regions. These regions have a well-established role in the hedonic control of food intake. On the other hand, it is not yet known whether POMC neurons and AgRP in the ARC participate in the modulation of neurotensinergic neurons in the LHA. Data from our laboratory and the literature demonstrate that rodents that are malnourished in the neonatal period have hyperphagic behavior in adulthood, however, the involvement of changes in the hedonic component of food intake has not yet been well clarified. This study aims to investigate the role of POMC and AgRP neurons on food intake and the modulation of mesolimbic pathways related to the hedonic component of feeding, via LHA neurons in mice subjected to neonatal nutritional programming. To carry out this study, we will use chemogenetic neuronal modulation, DREADD - (Designed Receptor Exclusively Activated by Designed Drugs), which consists of the expression of a receptor associated with the stimulatory Gq or inhibitory Gi protein, whose expression is dependent on the Cre recombinase enzyme. Stimulation of DREADD, Gq or Gi, occurs through intraperitoneal injection of CNO (clozapine-N-oxide). In the present study, AgRP-IRES-cre or POMC-cre mice will be used, which will receive bilateral injection of AAV-hSyn-DIO-hM3D(Gq)-mCherry or AAV-hSyn-DIO-hM4D(Gi)-mCherry in the ARC and subsequent treatment with CNO (1mg/kg i.p.), for stimulation or inhibition, respectively, of AgRP and POMC neurons. This study we to contribute to a better understanding of the effects of changes in the neonatal nutritional environment on the mechanisms involved with the food reward system and energy homeostasis in adult life.