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AgRP and POMC neurons and mesolimbic pathways in the control of feeding in neonatal nutritional programming. Ribeirão Preto 2018

Grant number: 18/12311-4
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): August 01, 2018
Effective date (End): April 30, 2019
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:José Antunes Rodrigues
Grantee:Juliana Tonietto Domingues
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/09799-1 - Energy balance and body fluid homeostasis control: from cells to the physiological systems, AP.TEM

Abstract

The prevalence of Obesity worldwide has increased significantly in the last decades, in the diverse age groups of the development. Obesity is characterized by the presence of excess body adiposity, being an independent risk factor for Coronary Artery Disease and for the development of the Metabolic Syndrome. Nutritional changes that occur during the developmental period of the individual may compromise energetic homeostasis in adult life. Prenatal and neonatal programming has been related to epigenetic alterations, which culminate in the alteration of the expression of genes important for the control of energy homeostasis. It is 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 (ARC) 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 expressing anorexigenic and orexigenic neuropeptides such as proopiomelanocortin (POMC) and agouti-related protein (AgRP), respectively. In addition, it has been demonstrated that leptin is also of great importance in the hedonic control of food intake, with action in neurons present in the lateral hypothalamic area (LHA, such as 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 and AgRP neurons from the ARC participate in the modulation of neurotensinergic neurons in the LHA, which express MC4R receptor, which binds to the alpha-MSH agonist and the endogenous AgRP antagonist. Data from our laboratory and the literature show that undernourished rodents in the neonatal period have hyperphagic behavior in adult life, however, the involvement of changes in the hedonic component of food intake has not yet been well understood. Our work aims to evaluate the participation of POMC and AgRP neurons in food intake and in the modulation of mesolimbic pathways related to the hedonistic component of the diet, via neurons present in the LHA, in undernourished mice in the neonatal period. To carry out this study we will use the modulation technique of chemogenetic neuronal activity, DREADD - (Designed Receptor Exclusively Activated by Designed Drugs), which consists of the expression of a receptor associated with the stimulatory Gq protein or inhibitory Gi, whose expression is dependent on the enzyme Cre recombinase. Stimulation of DREADD, Gq or Gi occurs by intraperitoneal injection of the innocuous CNO (clozapine-N-oxide). In the present study, AgRP-IRES-cre or POMC-cre mice receiving bilateral AAV-hSyn-DIO-hM3D (Gq) -mCherry or AAV-hSyn-DIO-hM4D (Gi) -mCherry mice injection will be used in the ARC and subsequent treatment with CNO (1mg/kg ip), for stimulation or inhibition, respectively, of the AgRP and POMC neurons. Thus, we intend to contribute to a better knowledge of the effects of changes in the neonatal nutritional environment in the mechanisms involved with the food reward system and energy homeostasis. (AU)