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Study of leptin functions during intrauterine and childhood stages in mice

Grant number: 14/11752-6
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): October 01, 2014
Effective date (End): March 31, 2018
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal researcher:Jose Donato Junior
Grantee:Angela Maria Ramos Lobo
Home 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


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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Scientific publications (14)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
BUONFIGLIO, DANIELLA C.; RAMOS-LOBO, ANGELA M.; SILVEIRA, MARINA A.; FURIGO, ISADORA C.; HENNIGHAUSEN, LOTHAR; FRAZAO, RENATA; DONATO, JR., JOSE. Neuronal STAT5 signaling is required for maintaining lactation but not for postpartum maternal behaviors in mice. Hormones and Behavior, v. 71, p. 60-68, . (13/21722-4, 14/11752-6, 12/12202-4)
BUONFIGLIO, DANIELLA C.; RAMOS-LOBO, ANGELA M.; FREITAS, VANESSA M.; ZAMPIERI, THAIS T.; NAGAISHI, VANESSA S.; MAGALHAES, MAGNA; CIPOLLA-NETO, JOSE; CELLA, NATHALIE; DONATO, JR., JOSE. Obesity impairs lactation performance in mice by inducing prolactin resistance. SCIENTIFIC REPORTS, v. 6, . (10/18086-0, 15/10992-6, 14/11752-6, 10/07699-1, 13/16374-7, 12/15517-6)
RAMOS-LOBO, ANGELA M.; FURIGO, ISADORA C.; TEIXEIRA, PRYSCILA D. S.; ZAMPIERI, THAIS T.; WASINSKI, FREDERICK; BUONFIGLIO, DANIELLA C.; DONATO, JR., JOSE. Maternal metabolic adaptations are necessary for normal offspring growth and brain development. PHYSIOLOGICAL REPORTS, v. 6, n. 5, . (16/20897-3, 14/11752-6, 15/10992-6, 12/15517-6)
PEDROSO, JOAO A. B.; DE MENDONCA, PEDRO O. R.; FORTES, MARCO A. S.; TOMAZ, IGOR; PECORALI, VITOR L.; AURICINO, THAIS B.; COSTA, ISMAEL C.; LIMA, LEANDRO B.; FURIGO, ISADORA C.; BUENO, DEBORA N.; et al. SOCS3 expression in SF1 cells regulates adrenal differentiation and exercise performance. Journal of Endocrinology, v. 235, n. 3, p. 207-222, . (10/18086-0, 12/23535-4, 13/21722-4, 14/11752-6, 14/50140-6, 15/10992-6)
FURIGO, ISADORA C.; MELO, HELEN M.; LYRA E SILVA, NATALIA M.; RAMOS-LOBO, ANGELA M.; TEIXEIRA, PRYSCILA D. S.; BUONFIGLIO, DANIELLA C.; WASINSKI, FREDERICK; LIMA, ELIANA R.; HIGUTI, ELIZA; PERONI, CIBELE N.; et al. Brain STAT5 signaling modulates learning and memory formation. Brain Structure & Function, v. 223, n. 5, p. 2229-2241, . (12/02388-3, 17/02983-2, 15/10992-6, 14/11752-6, 16/09679-4, 16/20897-3, 12/24345-4)
FURIGO, ISADORA C.; SUZUKI, MIRIAM F.; OLIVEIRA, JOAO E.; RAMOS-LOBO, ANGELA M.; TEIXEIRA, PRYSCILA D. S.; PEDROSO, JOAO A.; DE ALENCAR, AMANDA; ZAMPIERI, THAIS T.; BUONFIGLIO, DANIELLA C.; QUARESMA, PAULA G. F.; et al. Suppression of Prolactin Secretion Partially Explains the Antidiabetic Effect of Bromocriptine in ob/ob Mice. Endocrinology, v. 160, n. 1, p. 193-204, . (15/10992-6, 14/11752-6, 13/21722-4, 17/25281-3, 12/24345-4, 13/25032-2, 12/15517-6)
TEIXEIRA, PRYSCILA D. S.; RAMOS-LOBO, ANGELA M.; TAVARES, MARIANA ROSOLEN; WASINSKI, FREDERICK; FRAZAO, RENATA; DONATO JR, JOSE. Characterization of the onset of leptin effects on the regulation of energy balance. Journal of Endocrinology, v. 249, n. 3, p. 239-251, . (14/11752-6, 16/20897-3, 17/21840-8, 20/10102-9)
WASINSKI, FREDERICK; FURIGO, ISADORA C.; TEIXEIRA, PRYSCILA D. S.; RAMOS-LOBO, ANGELA M.; PERONI, CIBELE N.; BARTOLINI, PAOLO; LIST, EDWARD O.; KOPCHICK, JOHN J.; DONATO JR, JOSE. Growth Hormone Receptor Deletion Reduces the Density of Axonal Projections from Hypothalamic Arcuate Nucleus Neurons. Neuroscience, v. 434, p. 136-147, . (16/20897-3, 14/11752-6, 17/02983-2, 16/09679-4)
FURIGO, ISADORA C.; RAMOS-LOBO, ANGELA M.; FRAZAO, RENATA; DONATO, JR., J.. Brain STAT5 signaling and behavioral control. Molecular and Cellular Endocrinology, v. 438, n. C, p. 70-76, . (13/07908-8, 10/18086-0, 15/10992-6, 14/11752-6, 12/12202-4, 13/21722-4)
RAMOS-LOBO, ANGELA M.; TEIXEIRA, PRYSCILA D. S.; FURIGO, ISADORA C.; MELO, HELEN M.; LYRA E SILVA, NATALIA DE M.; DE FELICE, FERNANDA G.; DONATO, JR., JOSE. Long-term consequences of the absence of leptin signaling in early life. eLIFE, v. 8, . (14/11752-6, 15/10992-6, 16/09679-4)
PEDROSO, JOAO A. B.; RAMOS-LOBO, ANGELA M.; DONATO, JR., JOSE. SOCS3 as a future target to treat metabolic disorders. HORMONES-INTERNATIONAL JOURNAL OF ENDOCRINOLOGY AND METABOLISM, v. 18, n. 2, p. 127-136, . (17/02983-2, 14/11752-6, 13/25032-2)
TEIXEIRA, PRYSCILA D. S.; RAMOS-LOBO, ANGELA M.; FURIGO, ISADORA C.; DONATO, JR., JOSE. Brain STAT5 Modulates Long-Term Metabolic and Epigenetic Changes Induced by Pregnancy and Lactation in Female Mice. Endocrinology, v. 160, n. 12, p. 2903-2917, . (17/02983-2, 14/11752-6, 15/10992-6)
PEDROSO, JOAO A. B.; SILVEIRA, MARINA A.; LIMA, LEANDRO B.; FURIGO, ISADORA C.; ZAMPIERI, THAIS T.; RAMOS-LOBO, ANGELA M.; BUONFIGLIO, DANIELLA C.; TEIXEIRA, PRYSCILA D. S.; FRAZAO, RENATA; DONATO, JR., JOSE. Changes in Leptin Signaling by SOCS3 Modulate Fasting-Induced Hyperphagia and Weight Regain in Mice. Endocrinology, v. 157, n. 10, p. 3901-3914, . (10/18086-0, 13/07908-8, 15/10992-6, 14/11752-6, 12/12202-4, 13/21722-4, 13/25032-2, 12/15517-6)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
LOBO, Angela Maria Ramos. Study of leptin functions during intrauterine and infancy periods in mice.. 2018. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.

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