Long-term consequences of the absence of leptin signaling in early life

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Abstract

Leptin regulates energy balance and also exhibits neurotrophic effects during critical developmental periods. However, the actual role of leptin during development is not yet fully understood. To uncover the importance of leptin in early life, the present study restored leptin signaling either at the 4^th or 10^th week of age in mice formerly null for the leptin receptor (LepR) gene. We found that some defects previously considered irreversible due to neonatal deficiency of leptin signaling, including the poor development of arcuate nucleus neural projections, were recovered by LepR reactivation in adulthood. However, LepR deficiency in early life led to irreversible obesity via suppression of energy expenditure. LepR reactivation in adulthood also led to persistent reduction in hypothalamic Pomc, Cartpt and Prlh mRNA expression and to defects in the reproductive system and brain growth. Our findings revealed that early defects in leptin signaling cause permanent metabolic, neuroendocrine and developmental problems.

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Individual values were plotted in each figure and source data files have also been included.

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Angela M Ramos-Lobo

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

Competing interests
The authors declare that no competing interests exist.
Pryscila DS Teixeira

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

Competing interests
The authors declare that no competing interests exist.
Isadora C Furigo

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

Competing interests
The authors declare that no competing interests exist.
Helen M Melo

Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

Competing interests
The authors declare that no competing interests exist.
Natalia M Lyra e Silva

Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

Competing interests
The authors declare that no competing interests exist.
Fernanda G De Felice

Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

Competing interests
The authors declare that no competing interests exist.
Jose Donato

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

For correspondence
jdonato@icb.usp.br

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4166-7608

Funding

Fundação de Amparo à Pesquisa do Estado de São Paulo (15/10992-6)

Jose Donato

Fundação de Amparo à Pesquisa do Estado de São Paulo (14/11752-6)

Angela M Ramos-Lobo

Fundação de Amparo à Pesquisa do Estado de São Paulo (16/09679-4)

Isadora C Furigo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were carried out in compliance with NIH guidelines for the care and use of laboratory animals and were previously approved by our Institutional Animal Ethics Committee (protocol number 137/2013).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.