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The role of hypothalamic stearoil-CoA 2 (SCD2) in neurogenesis de novo

Grant number: 14/24050-0
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): March 01, 2015
Effective date (End): December 31, 2016
Field of knowledge:Biological Sciences - Physiology - General Physiology
Principal Investigator:Licio Augusto Velloso
Grantee:Felipe Corrêa da Silva
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

Abstract

The control of the metabolism is largely done by the hypothalamus. Some neurons in this region can connect signals from other brain regions and integrate them to the adipose peripheral hormones leptin and insulin which are the main responsible factors involved in the long term body mass control. In experimental rodents, high fat diet consumption activates the innate immune receptor TLR4 in hypothalamus. The inflammatory response compromises leptin and insulin signaling in this brain region and can induces apoptosis of neurons which control hunger and satiety. As the result, a disruption in the fine tune of food ingestion and energy expenditure leads obesity phenotype and a bigger difficult to treat the disease. Some works with MRI suggest similar results for obese humans. The description of a hypothalamic neurogenic niche in adult mice and the inability of genetic, pharmacological and clinical interventions to change obesity phenotype lead us to suppose that one of the most promising therapeutic approaches could be the induction of neurogenesis to restore the numeric and functional neurons dysfunction in high fat obese mice. For this reason we are interested in the knowledge of the mechanisms which defines cells proliferation and differentiation rates in hypothalamus. We have already known that de novo lipogenesis contributes significantly for the cell proliferation, especially in synthesis of membrane phospholipids. The enzyme fatty acid synthase FASn were previously described as a key step in adult neurogenesis in other brains regions. Another important enzyme involved in fatty acid desaturation during de novo lipogenesis, stearoyl-CoA SCD2, broadly expressed in the hypothalamus of high fat obese mice were not explored in the context of neurogenesis. We propose here to investigate the role hypothalamic SCD2 in neurogenesis of adult mice. For this purpose, we will use five week old male CH3/HEPAS fed on a chow or a high fat diet during four weeks. One group of animals will receive antisense for SCD2 during the last two weeks and the other group will receive a microinjection of lentivirus to over express or inhibit the hypothalamic SCD2 at the beginning of the treatment. The effectiveness of these interventions will be evaluated by western blotting and during all the treatment food intake and body weight will be monitored. During the first two weeks of diet the animals will receive intraperitoneally injection of BrdU 50 mg/kg/day twice a day to investigate cell proliferation in hypothalamus by immunofluorescence microscopy. At the end of the treatments we will assess the energy expenditure and the glucose metabolism of the animals. We believe that SCD2 plays a key role in hypothalamic neurogenesis of mice and these new neurons can contribute to the metabolic balance. Therefore, understanding the contribution of this enzyme in the cell proliferation and differentiation may help the development of therapeutic approaches to control and combat the obesity.