Hypothalamic sites of leptin action linking metabolism and reproduction - PubMed (original) (raw)

Review

Hypothalamic sites of leptin action linking metabolism and reproduction

José Donato Jr et al. Neuroendocrinology. 2011.

Abstract

A critical amount of energy reserve is necessary for puberty initiation, for normal sexual maturation and maintenance of cyclicity and fertility in females of most species. Therefore, the existence of circulating metabolic cues which directly modulate the hypothalamus-pituitary-gonad axis is predictable. The adipocyte-derived hormone leptin is one of these cues having been studied extensively in the context of regulating the reproductive physiology. Humans and mice lacking leptin (ob/ob) or leptin receptor (LepR, db/db) are infertile. Leptin administration to leptin-deficient subjects and ob/ob mice induces puberty and restores fertility. LepR is expressed in brain, pituitary gland and gonads, but studies using genetically engineered mouse models determined that the brain plays a major role. Recently, it has been made clear that leptin acts indirectly on gonadotropin-releasing hormone (GnRH)-secreting cells via actions on interneurons. However, the exact site(s) of leptin action has been difficult to determine. In this review, we discuss the recent advances in the field focused on the identification of potential site(s) or specific neuronal populations involved in leptin's effects in the neuroendocrine reproductive axis.

Copyright © 2010 S. Karger AG, Basel.

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Figures

Fig. 1

Fig. 1

Comparative distribution of neurons expressing GnRH and of neurons expressing LepR reporter gene. Neurons expressing LepR were visualized using LepR-IRES-Cre mice crossed with tdTomato reporter mice (B6.Cg-_Gt(ROSA)26Sor_tm9(CAG-tdTomato)Hze/J, JAX® mice). a–c Fluorescent photomicrograph showing the distribution of neurons expressing LepR (a, c) and of neurons expressing GnRH immunoreactivity (GnRH-ir, b, c) in the medial preoptic area (MPA). d–f Higher magnification of a–c. Observe that some neurons which express LepR are intermingled with GnRH neurons in the MPA (c, f). ac = Anterior commissure; MS = medial septal nucleus; ovlt = vascular organ of lamina terminalis. Scale bar: a–c 800 μm; d–f 200 μm.

Fig. 2

Fig. 2

Distribution of neurons expressing LepR in the NTS and PVH. Neurons expressing LepR were visualized using LepR-IRES-Cre mice crossed with tdTomato reporter mice (B6.Cg-_Gt(ROSA)26Sor_tm9(CAG-tdTomato)Hze/J, JAX® mice). a Fluorescent photomicrograph showing neurons expressing LepR in the NTS. Observe the close proximity with the AP. b Fluorescent photomicrograph showing fibers originating from LepR-positive neurons in the PVH. Observe the absence of cell bodies containing the reporter gene within the limits of the PVH. 3v = Third ventricle; DMV = dorsal motor nucleus of the vagus nerve; SCh = suprachiasmatic nucleus. Scale bar: a 200 μm; b 400 μm.

Fig. 3

Fig. 3

Comparative distribution of estrogen receptor-α immunoreactivity (ERα-ir) and leptin-responsive neurons in the VMH. a Bright-field photomicrograph showing the distribution of ERα-ir in the VMH. Observe that neurons expressing ERα-ir are enriched in the ventrolateral subdivision of the VMH (VMHvl). b Bright-field photomicrograph showing the distribution of leptin-responsive neurons in the VMH. Leptin-responsive neurons were visualized by leptin-induced phosphorylation of STAT3 immunoreactivity (pSTAT3-ir). Observe that leptin-responsive neurons are enriched in the dorsomedial subdivision of the VMH (VMHdm). 3v = Third ventricle; Arc = arcuate nucleus; f = fornix. Scale bar: 400 μm.

Fig. 4

Fig. 4

Distribution of neurons expressing LepR in the PMV. Neurons expressing LepR were visualized using LepR-IRES- Cre mice crossed with tdTomato reporter mice (B6.Cg-_Gt(ROSA) 26Sor_tm9(CAG-tdTomato)Hze/J, JAX® mice). a, b Fluorescent photomicrographs showing the distribution of LepR in the PMV. c Fluorescent photomicrographs showing the presence of GnRH-ir in neurons at most caudal levels of the mediobasal hypothalamus. d Higher magnification of b and c (merged image) showing that GnRH neurons are outside the borders of the PMV. 3v = Third ventricle; Arc = arcuate nucleus. Scale bar: a 800 μm; b, c 400 μm; d 200 μm.

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