Chehab F. Leptin and reproduction: past milestones, present undertakings and future endeavors. Journal of Endocrinology. http://joe.endocrinology-journals.org/content/early/2014/08/11/JOE-14-0413.abstract
The association between leptin and reproduction originated with the leptin-mediated correction of sterility in ob/ob mice and initiation of reproductive function in normal female mice. The uncovering of a central leptin pathway regulating food intake prompted the dissection of neuroendocrine mechanisms involving leptin in the metabolic control of reproduction. The absence of leptin receptors on GnRH neurons incited a search for intermediary neurons situated between leptin responsive and GnRH neurons.
This review addresses the most significant findings that have furthered our understanding of recent progress in this new field. The role of leptin in puberty was impacted by the discovery of neurons that co-express kisspeptin, neurokinin B and dynorphin and that could act as leptin intermediates. Furthermore, the identification of first-order leptin-responsive neurons in the premammilary ventral nucleus and other brain regions opens new avenues to explore their relationship to GnRH neurons. Central to these advances is the unveiling that AgRP/NPY neurons project onto GnRH and kisspeptin neurons, allowing a crosstalk between food intake and reproduction.
Finally, whereas puberty is a state of leptin sensitivity, mid-gestation represents a state of leptin resistance aimed at building energy stores to sustain pregnancy and lactation. Mechanisms underlying leptin resistance in pregnancy have lagged, however the establishment of this natural state is significant.
Reproduction and energy balance are tightly controlled and backed up by redundant mechanisms that are critical for the survival of our species. It will be the goal of the next decade to shed new light on these complex and essential pathways.
Schematic diagram and proposed model for the metabolic regulation and coordination of the leptin mediated reproductive and nutritional axes.
Leptin, insulin and IGF-1 are shown as the most critical circulatory factors that act on hypothalamic and other brain networks to regulate food intake and GnRH secretion.
The pathway, rich in redundancies, depicts the various direct and indirect inputs that converge on GnRH neurons.
The crosstalks of the reproductive and nutritional axes are represented by the projections of the AgRP/NPY and POMC neurons to the KNDy neurons and by the AgRP/NPY neurons onto GnRH neurons.
The first order leptin responsive neurons in the PMV and other hypothalamic areas are denoted with a thick green arrow to highlight their essential reproductive function and the release of the NO neurotransmitter.
Ligands and receptors are shown on each set of neurons and green/red arrows represent stimulatory and inhibitory effects, respectively.
The postulated elusive leptin intermediate neurons are denoted with a question mark. Acronyms in the figure are found in the text.
The association between leptin and reproduction originated with the leptin-mediated correction of sterility in ob/ob mice and initiation of reproductive function in normal female mice. The uncovering of a central leptin pathway regulating food intake prompted the dissection of neuroendocrine mechanisms involving leptin in the metabolic control of reproduction. The absence of leptin receptors on GnRH neurons incited a search for intermediary neurons situated between leptin responsive and GnRH neurons.
This review addresses the most significant findings that have furthered our understanding of recent progress in this new field. The role of leptin in puberty was impacted by the discovery of neurons that co-express kisspeptin, neurokinin B and dynorphin and that could act as leptin intermediates. Furthermore, the identification of first-order leptin-responsive neurons in the premammilary ventral nucleus and other brain regions opens new avenues to explore their relationship to GnRH neurons. Central to these advances is the unveiling that AgRP/NPY neurons project onto GnRH and kisspeptin neurons, allowing a crosstalk between food intake and reproduction.
Finally, whereas puberty is a state of leptin sensitivity, mid-gestation represents a state of leptin resistance aimed at building energy stores to sustain pregnancy and lactation. Mechanisms underlying leptin resistance in pregnancy have lagged, however the establishment of this natural state is significant.
Reproduction and energy balance are tightly controlled and backed up by redundant mechanisms that are critical for the survival of our species. It will be the goal of the next decade to shed new light on these complex and essential pathways.
Schematic diagram and proposed model for the metabolic regulation and coordination of the leptin mediated reproductive and nutritional axes.
Leptin, insulin and IGF-1 are shown as the most critical circulatory factors that act on hypothalamic and other brain networks to regulate food intake and GnRH secretion.
The pathway, rich in redundancies, depicts the various direct and indirect inputs that converge on GnRH neurons.
The crosstalks of the reproductive and nutritional axes are represented by the projections of the AgRP/NPY and POMC neurons to the KNDy neurons and by the AgRP/NPY neurons onto GnRH neurons.
The first order leptin responsive neurons in the PMV and other hypothalamic areas are denoted with a thick green arrow to highlight their essential reproductive function and the release of the NO neurotransmitter.
Ligands and receptors are shown on each set of neurons and green/red arrows represent stimulatory and inhibitory effects, respectively.
The postulated elusive leptin intermediate neurons are denoted with a question mark. Acronyms in the figure are found in the text.
