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Hypothalamic responsiveness to leptin and ghrelin in neonatal overfed programmed rats

Grant number: 12/04211-3
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): June 01, 2012
Effective date (End): June 30, 2015
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Lucila Leico Kagohara Elias
Grantee:Paula Beatriz Marangon
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


Programming can be defined as a stimulus during a critical period of development, when the central nervous system is still plastic and may show susceptibility to environment effects, which may affect adult life. A model of neonatal programming largely used is the modification of the litter size, which causes an increase in body weight in animals raised in small litters, and this phenotype persists in adult life accompanied by leptin resistance. Leptin is synthesized, mainly, in white adipocytes and acts in the hypothalamus inhibiting orexigenic neurons and activating anorexigenic neurons. It has been demonstrated that modifications in circulating leptin levels during development can change hypothalamic circuits' maturation, causing permanent appetite modifications and sympathetic nervous system (SNS) activation. Ghrelin is released by specialized endocrine cells present in the stomach and acts activating NPY/AgRP neurons. Therefore, using the neonatal small litter programming, this work aims to investigate central leptin and ghrelin sensitivity, molecular mechanisms involved in leptin hypothalamic resistance, as well as to verify SNS activity in brown adipose tissue. For this purpose, male Wistar rats will be divided into two groups after birth: small litters, with 3 pups, and normal litters, with 8 pups. During lactation body weight gain will be analyzed twice a week. After weaning (21 days), food intake and body weight gain will be analyzed twice every week until 60 days of life. Animals will be decapitated at 21 or 60 days and blood, brain, white and brown adipose tissue and adrenal glands will be collected for hormonal evaluation, gene expression and protein expression analysis. Hypothalamic neuronal activation will be analyzed after leptin or ghrelin administration. To attain these purposes we will use specific immunoassays, real time PCR and Western blotting.