| Grant number: | 14/11752-6 |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| Start date: | October 01, 2014 |
| End date: | March 31, 2018 |
| Field of knowledge: | Biological Sciences - Physiology - Physiology of Organs and Systems |
| Agreement: | Coordination of Improvement of Higher Education Personnel (CAPES) |
| Principal Investigator: | Jose Donato Junior |
| Grantee: | Angela Maria Ramos Lobo |
| Host Institution: | Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil |
| Associated scholarship(s): | 16/22867-4 - Developmental influences on brown adipose tissue maturation and function, BE.EP.DR |
Abstract Leptin is an essential hormone for the regulation of energy balance in adults through its action on specific neuron populations expressing leptin receptor (LepR). The obesity and overweight are both leading causes of death worldwide and specifically in Brazil. For the first time, over half of its population is overweight or obese. Most obese individuals are leptin resistant. However, some studies suggest that during the neonatal stage and early youth leptin has different physiological functions from those observed in adults, probably more related with neuronal development. For example, overweight at birth or childhood obesity are related with high incidence of metabolic disturbs in later life. In these cases, it is possible that leptin function during those periods is altered, representing one of the possible mechanisms of the "fetal programming". Therefore, the objective of the present study is to obtain a better understanding of leptin functions during the intrauterine, neonatal and early childhood stages as well as the consequences in adulthood due to its absence in those critical periods. Initially, we will use leptin receptor deficient mice (db/db mice) to determine the exact moment when their phenotype related to obesity and hyperphagia is expressed. Then, we will generate and characterize genetically modified mice using the tamoxifen-inducible Cre-LoxP system. In order to do so, we will use Ubiquitin-CreERT2 mice with Cre Recombinase function in all cells inducible by tamoxifen treatment. These mice will be paired with mice bearing a translation blocker, flanked by loxP sites, downstream the Lepr gene. The result of this breeding will be LepR deficient mice until they are treated with tamoxifen. LepR activation will be possible in any developmental stage, such as intrauterine, neonatal, early and late childhood or adulthood. Thus, we will be able to study the deficits caused by the lack of leptin signaling during critical periods of development. Mice will be genotyped (extracting DNA from tail), selected by gender, and genotype and studied during different life stages to determine parameters of energetic metabolism, such as body weight, food and water intake, energy expenditure, gross motor activity and body composition. Animals will be euthanized and their blood will be collected for metabolites and hormonal dosage. Hypothalamus, liver, skeletal muscle and fat tissues will be collected for different protein and RNAm analyses. In vivo tests will be performed in a group of mice to determine insulin and leptin resistance and tolerance to glucose. Histological analyses will be performed in order to determine the development of projections in hypothalamic neurons. Finally, behavioral tests will be performed to evaluate memory, anxiety, stress and other cognitive aspects. This project can potentially help to understand a less studied, but potentially critically important function of leptin: its effects on the development of the nervous system. Therefore, this study can provide several pieces of evidence the role of leptin signaling during development and its impact on metabolic diseases or disturbances in the organism later in adulthood. (AU) | |
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