Study of leptin functions during intrauterine and infancy periods in mice.

Author(s)

Angela Maria Ramos Lobo

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2018-05-10

Examining board members

José Donato Júnior; Gabriel Forato Anhê; William Tadeu Lara Festuccia; Patrícia de Oliveira Prada; Lício Augusto Velloso

• Advisor: José Donato Júnior

Abstract

Leptin is an essential hormone for energy balance control in adults, through its action on specific neural populations that express its receptor (Lepr). Currently, obesity and overweight constitute the fifth cause of death worldwide and in Brazil, for the first time more than half of its population is overweight. A common feature in obese people is leptin resistance. However, some studies suggest that during neonatal and infancy periods leptin has physiological effects different than those observed in adults, related to neuronal development. For example, excessive weight at birth or childhood obesity is related to higher incidence of metabolic disorders in the future. In these cases, leptins functions in early life might be altered, representing a possible mechanism of fetal programming. The objective of this study is to better understand the functions of leptin during development as well as the long-term consequences of its absence in early life. For this, a LoxP-flanked transcription-blocking cassette was inserted in the Lepr gene to generate mice null for the Lepr. They were bred with animals expressing Cre-ERT2 fusion protein under the human ubiquitin C promoter sequence. Consequently, tamoxifen injections can induce Cre Recombinase activity and restore Lepr gene expression in adult or young Ubi-LepRNull mice. Adult mice treated with tamoxifen recover some physiological functions but others seem to partially recovered or not recovered at all. They recovered food intake and reversed the obese phenotype, but remained heavier, with lower energy expenditure and locomotor activity than lean controls. Adiposity and leptinemia were improved but not restored. Their glycemic control remained altered as well as the reproduction axis in females and males. Brain mass was reduced in obese mice and partially recovered after Lepr reactivation. Reactivation before weaning prevented the obese phenotype and restored glycemic control; however energy expenditure, leptinemia and brain mass remained altered. These results strongly suggest that leptin signaling in early life is fundamental for the development of metabolic and neurological parameters and that metabolic programming might influence those parameters. (AU)

• FAPESP's process: 14/11752-6 - Study of leptin functions during intrauterine and childhood stages in mice
• Grantee: Angela Maria Ramos Lobo
• Support Opportunities: Scholarships in Brazil - Doctorate