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Investigation of metabolic programming through different approaches

Grant number: 15/10992-6
Support Opportunities:Regular Research Grants
Duration: February 01, 2016 - July 31, 2017
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Jose Donato Junior
Grantee:Jose Donato Junior
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil


The metabolic programming can be defined as permanent changes in animal physiology and metabolism that were caused by periods in which the organism has been subjected to some forms of stress. Metabolic programming has been studied in more details during embryo development, when, for example, nutritional changes in the mother are able to predispose embryos/fetuses to an increased risk of metabolic diseases in adulthood, such as obesity and diabetes mellitus. Despite the growing recognition of the importance of metabolic programming in the etiology of metabolic disease later in life, little is known about the mechanisms involved in this phenomenon. Leptin is a hormone essential for the energy balance control. However, some studies suggest that during the neonatal period and infancy leptin has distinct functions from those observed in adults, probably more related to neural development. Therefore, it is possible that the function of leptin during development is altered in conditions of deficiency (maternal malnutrition) or abundance of nutrients (maternal obesity), representing one of the possible mechanisms of the so-called fetal programming. Therefore, we propose to study metabolic programming through three different approaches in order to get a better understanding of the factors and mechanisms involved in this phenomenon. In the first subproject, we intend to study the consequences of the lack of leptin signaling during the development of the nervous system. Therefore, we used the Cre-LoxP system to produce genetically modified mice that are deficient of leptin receptors, but whose expression can be temporally restored. In this way, we will study possible deficits caused by the absence of leptin signaling during critical periods of development in the regulation of energy balance, glucose homeostasis, behaviors, cognition and changes in neural development. In the second subproject will evaluate the importance of metabolic adaptations during pregnancy (i.e., increase in mothers of food intake, adiposity and insulin and leptin resistance) for offspring metabolic programming. Therefore, we will use a mouse model, recently characterized by our group (Zampieri et al., Mol Metab, 2015), whose gestational metabolic changes were prevented or alleviated. In this proposal, we will evaluate the possible impact on the offspring. In the last subproject, we will assess whether the metabolic programming occurs in adult mice. Pregnancy is a model that promotes extensive adaptation in the female organism and there is evidence that pregnancy can permanently alter the response to certain hormones and, in some cases, predispose women to obesity and diabetes. Thus, we aimed to determine whether the experience of pregnancy, followed or not by lactation, can cause metabolic programming and affect specific neural systems. These experiments may help in understanding the mechanisms involved in the etiology of metabolic diseases, which have become a worldwide health problem. (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)
SILVEIRA, MARINA AUGUSTO; FURIGO, ISADORA C.; ZAMPIERI, THAIS T.; BOHLEN, TABATA M.; DE PAULA, DANIELLA G.; FRANCI, CELSO RODRIGUES; DONATO, JR., JOSE; FRAZAO, RENATA. STAT5 signaling in kisspeptin cells regulates the timing of puberty. Molecular and Cellular Endocrinology, v. 448, n. C, p. 55-65, . (15/20198-5, 12/12202-4, 15/10992-6, 13/07908-8, 13/21722-4, 15/14588-5)
BOHLEN, TABATA MARIZ; SILVEIRA, MARINA AUGUSTO; BUONFIGLIO, DANIELLA DO CARMO; FERREIRA-NETO, HILDEBRANDO CANDIDO; CIPOLLA-NETO, JOSE; DONATO, JR., JOSE; FRAZAO, RENATA. A Short-Day Photoperiod Delays the Timing of Puberty in Female Mice via Changes in the Kisspeptin System. FRONTIERS IN ENDOCRINOLOGY, v. 9, . (15/26190-6, 12/12202-4, 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, . (16/20897-3, 14/11752-6, 12/02388-3, 16/09679-4, 15/10992-6, 17/02983-2, 12/24345-4)
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.; 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, . (13/25032-2, 14/11752-6, 15/10992-6, 12/15517-6, 13/21722-4, 17/25281-3, 12/24345-4)
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, 13/16374-7, 14/11752-6, 15/10992-6, 12/15517-6, 10/07699-1)
DONATO, JR., JOSE; FRAZAO, RENATA. Interactions between prolactin and kisspeptin to control reproduction. ARCHIVES OF ENDOCRINOLOGY METABOLISM, v. 60, n. 6, p. 587-595, . (15/10992-6, 13/07908-8)
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, 12/15517-6, 15/10992-6, 14/11752-6)
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, . (15/10992-6, 14/11752-6, 17/02983-2)
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, . (13/25032-2, 10/18086-0, 14/11752-6, 12/12202-4, 15/10992-6, 13/07908-8, 12/15517-6, 13/21722-4)
LIMA, LEANDRO B.; METZGER, MARTIN; FURIGO, ISADORA C.; DONATO, JR., J.. Leptin receptor-positive and leptin receptor-negative proopiomelanocortin neurons innervate an identical set of brain structures. Brain Research, v. 1646, p. 366-376, . (15/10992-6, 10/18086-0, 12/02388-3)
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, . (14/11752-6, 12/12202-4, 10/18086-0, 15/10992-6, 13/07908-8, 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, . (15/10992-6, 14/11752-6, 16/09679-4)

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