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Role of the transcription factor IRX3 in inducing hypothalamic neurogenesis in adult mice

Grant number: 14/07496-4
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): June 01, 2015
Effective date (End): November 07, 2019
Field of knowledge:Biological Sciences - Physiology
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Licio Augusto Velloso
Grantee:Thiago Matos Ferreira de Araujo
Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:13/07607-8 - OCRC - Obesity and Comorbidities Research Center, AP.CEPID
Associated scholarship(s):16/18908-7 - The impact of inhibiton of transcription factor IRX3 in AgRP or POMC neurons in energy metabolism, BE.EP.PD

Abstract

Obesity results from the pathological accumulation of fatty acids in the adipose tissue, leading to increased morbidity. Currently, obesity affects an increasing number of people in the planet, affecting life quality and longevity and, thus, impacting on medical and economical status of the contemporaneous populations. The development of the obese phenotype results from the loss of a coordinated control of caloric intake and energy expenditure. Genetic, environmental, metabolic and hormonal factors contribute to the genesis of obesity, but the complete elucidation of the pathophysiology of this disease is still lacking. The hypothalamus plays a major role in whole body energy homeostasis. Neurons present in hypothalamic nuclei are interconnected and control the neural responses that coordinate the search for food and a number of mechanisms that ultimately promote energy expenditure. The arcuate nucleus is particularly important in this context because it harbors neurons that respond to peripheral signals reflecting the energy status of the organism. Two subpopulations of neurons of the arcuate nucleus are specially involved in this regulation, the orexigenic, NPY expressing and the anorexigenic, POMC expressing neurons. The importance of these neurons if mostly due to the fact that they express receptors for leptin and insulin, the main hormones involved in the control of whole body energy status. Experimental studies have shown that, during the development of obesity, neurons of the hypothalamus become resistant to the leptin and insulin signals because of the induction of a saturated fatty acid-induced inflammation. One of the outcomes of such inflammatory activity is the induction of apoptosis of hypothalamic neurons. Recent studies have shown that POMC neurons are the main targets of diet-induced apoptosis, which can generate disequilibrium in the subpopulations of orexigenic and anorexigenic neurons, therefore, contributing to the perpetuation and irreversibility of obesity. Studies undertaken during the last ten years have provided evidence for the existence of adult neurogenesis in response to certain stimuli. Not all regions of the brain can undergo neurogenesis. Most of the initial studies have shown neurogenesis in the hippocampus; however, recently hypothalamic neurogenesis was also described. Of notice, satuared fatty acids present in the diet can induce hypothalamic neurogenesis; though, in this case, NPY neurons are the ones mostly generated. In a recent study (FAPESP grant 2009/53606-8, unpublished), our group has shown that unsaturated fatty acids induce the neurogenesis of predominantly POMC neurons in the hypothalamus. As a progressive unbalance between orexigenic and anorexigenic neurons may play a role in the development of obesity, the search for methods to reestablish such equilibrium seem to be important in order to reverse the phenotype. The objective of the present study is to evaluated diet-induced hypothalamic neurogenesis and its relation with the expression of the transcription factor IRX3. A recent study has shown that IRX3 is involved in the development of obesity. Moreover, IRX3 is involved in the neurogenesis in other regions of the brain. If IRX3 were indeed related to hypothalamic neurogenesis induced by dietary factors, the regulation of its expression may become a potential attractive target for the treatment of obesity. (AU)