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

• Grant number: 14/24050-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2015
• End date: December 31, 2016
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: Licio Augusto Velloso
• Grantee: Felipe Corrêa da Silva
• Host 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 long-term body mass control. In experimental rodents, high-fat diet consumption activates the innate immune receptor TLR4 in the hypothalamus. The inflammatory response compromises leptin and insulin signaling in this brain region and can induce apoptosis of neurons, which control hunger and satiety. As the result, a disruption in the fine-tune of food ingestion and energy expenditure leads to obesity phenotype and a bigger difficulty 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 define cells proliferation, and differentiation rates in the hypothalamus. We have already known that de novo lipogenesis contributes significantly to cell proliferation, especially in the synthesis of membrane phospholipids. The enzyme fatty acid synthase FASn was 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 of hypothalamic SCD2 in the neurogenesis of adult mice. For this purpose, we will use a five-week-old male CH3/HEPAS fed on chow or a high-fat diet for four weeks. One group of animals will receive antisense for SCD2 during the last two weeks and the other group will receive microinjection of lentivirus to overexpress 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 the 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 the hypothalamic neurogenesis of mice and these new neurons can contribute to the metabolic balance. Therefore, understanding the contribution of this enzyme in cell proliferation and differentiation may help the development of therapeutic approaches to control and combat obesity. (AU)