Leptin Signaling in Kiss1 Neurons Arises after Pubertal Development

Roberta M. Cravo, Renata Frazao, Mario Perello, Sherri Osborne-Lawrence, Kevin W. Williams, Jeffery M. Zigman, Claudia Vianna, Carol F. Elias

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

The adipocyte-derived hormone leptin is required for normal pubertal maturation in mice and humans and, therefore, leptin has been recognized as a crucial metabolic cue linking energy stores and the onset of puberty. Several lines of evidence have suggested that leptin acts via kisspeptin expressing neurons of the arcuate nucleus to exert its effects. Using conditional knockout mice, we have previously demonstrated that deletion of leptin receptors (LepR) from kisspeptin cells cause no puberty or fertility deficits. However, developmental adaptations and system redundancies may have obscured the physiologic relevance of direct leptin signaling in kisspeptin neurons. To overcome these putative effects, we re-expressed endogenous LepR selectively in kisspeptin cells of mice otherwise null for LepR, using the Cre-loxP system. Kiss1-Cre LepR null mice showed no pubertal development and no improvement of the metabolic phenotype, remaining obese, diabetic and infertile. These mice displayed decreased numbers of neurons expressing Kiss1 gene, similar to prepubertal control mice, and an unexpected lack of re-expression of functional LepR. To further assess the temporal coexpression of Kiss1 and Lepr genes, we generated mice with the human renilla green fluorescent protein (hrGFP) driven by Kiss1 regulatory elements and crossed them with mice that express Cre recombinase from the Lepr locus and the R26-tdTomato reporter gene. No coexpression of Kiss1 and LepR was observed in prepubertal mice. Our findings unequivocally demonstrate that kisspeptin neurons are not the direct target of leptin in the onset of puberty. Leptin signaling in kisspeptin neurons arises only after completion of sexual maturation.

Original languageEnglish (US)
Article numbere58698
JournalPLoS One
Volume8
Issue number3
DOIs
StatePublished - Mar 7 2013

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Kisspeptins
Leptin Receptors
Leptin
leptin
Neurons
neurons
mice
Puberty
Genes
puberty
Renilla
Sexual Maturation
Arcuate Nucleus of Hypothalamus
Green Fluorescent Proteins
Redundancy
Reporter Genes
Adipocytes
Knockout Mice
Cues
Fertility

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Cravo, R. M., Frazao, R., Perello, M., Osborne-Lawrence, S., Williams, K. W., Zigman, J. M., ... Elias, C. F. (2013). Leptin Signaling in Kiss1 Neurons Arises after Pubertal Development. PLoS One, 8(3), [e58698]. https://doi.org/10.1371/journal.pone.0058698

Leptin Signaling in Kiss1 Neurons Arises after Pubertal Development. / Cravo, Roberta M.; Frazao, Renata; Perello, Mario; Osborne-Lawrence, Sherri; Williams, Kevin W.; Zigman, Jeffery M.; Vianna, Claudia; Elias, Carol F.

In: PLoS One, Vol. 8, No. 3, e58698, 07.03.2013.

Research output: Contribution to journalArticle

Cravo, RM, Frazao, R, Perello, M, Osborne-Lawrence, S, Williams, KW, Zigman, JM, Vianna, C & Elias, CF 2013, 'Leptin Signaling in Kiss1 Neurons Arises after Pubertal Development', PLoS One, vol. 8, no. 3, e58698. https://doi.org/10.1371/journal.pone.0058698
Cravo, Roberta M. ; Frazao, Renata ; Perello, Mario ; Osborne-Lawrence, Sherri ; Williams, Kevin W. ; Zigman, Jeffery M. ; Vianna, Claudia ; Elias, Carol F. / Leptin Signaling in Kiss1 Neurons Arises after Pubertal Development. In: PLoS One. 2013 ; Vol. 8, No. 3.
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