Novel actions of kisspeptin signaling outside of GnRH-mediated fertility: a potential role in energy balance

Kisspeptin, encoded by Kiss1 gene expressing neurons in the hypothalamus, is a requisite for fertility and now appears critical in the regulation of energy balance. Kisspeptin neurons, particularly those in the arcuate nucleus (ARC), receive information directly and indirectly from a diverse array of brain regions including the bed nucleus of the stria terminalis, amygdala, interpeduncular nucleus, hippocampus, and cortex. On the other hand, kisspeptin neuron projections clearly extend to GnRH neuron cell bodies in rodents, sheep, and primates and beyond to other—non-GnRH—brain areas. Kiss1r, the kisspeptin receptor, is expressed on GnRH neurons and also in additional brain areas and peripheral tissues, indicating a nonreproductive role. Kisspeptin neurons clearly receive signals pertinent to deviations in energy balance but are now recognized as a novel neuroendocrine player in the fine balance of energy intake and expenditure. Mice that have a dysfunctional gene for Kiss1r develop an obese and diabetic phenotype. The mechanism behind this altered metabolic state is still mostly unknown; however, Kiss1r expression in the pancreas and brown adipose tissue is clearly functional and required for normal glucose tolerance and energy expenditure, respectively. Kisspeptin neurons in the ARC also participate in the generation of circadian rhythms, specifically those concerning food intake and metabolism, offering a potential explanation for the obesity in Kiss1r knockout mice. Overall, the discoveries of new mechanistic roles for kisspeptin in both normal and pathophysiologic states of energy balance may lead to further understating of obesity prevalence and novel therapeutic targets and interventions.