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Fasting suppresses functioning of the hypothalamic-pituitary-gonadal (HPG) axis by mechanisms that are incompletely understood. In 2003, hypothalamic kisspeptin-Kiss1r signaling was discovered to play a significant role in regulating the HPG axis. We have recently shown that in adult male macaques, short-term fasting attenuates the response of the HPG axis to an exogenous kisspeptin challenge. In the present study, we explored the mechanism underlying this attenuated response by examining the modulation of the hypothalamic expression of Kiss1 and Kiss1r under short-term fasting and normal feeding conditions in the adult male macaques. Hypothalamic mRNA was extracted from normal fed (n=3) and 48-h fasted (n=3) monkeys. Kiss1, Kiss1r, and GnRH1 mRNA was quantified by reverse transcription followed by real-time polymerase chain reaction. In addition, blood samples were collected for measurement of plasma concentrations of glucose, cortisol, leptin, and testosterone. In contrast to fed animals, plasma glucose, leptin, and testosterone levels decreased and cortisol levels increased in fasted animals. The hypothalamic expression of Kiss1 and Kiss1r mRNA was significantly lower (P<0.05) in fasted monkeys compared to fed monkeys while hypothalamic GnRH1 mRNA expression was comparable between the two groups. Thus, our results demonstrate that expression of hypothalamic Kiss1 and Kiss1r decrease after a short-term fasting in monkeys. This decrease may contribute to the suppression of the HPG axis during fasting conditions in primates. In addition, our finding of lower expression of Kiss1r in fasted monkeys provides an explanation for the attenuation in the HPG axis response to peripheral kisspeptin challenge during short-term fasting.

Recently, kisspeptin (KP) and gonadotropin inhibitory hormone (GnIH), two counteracting neuropeptides, have been acknowledged as significant regulators of reproductive function. KP stimulates reproduction while GnIH inhibits it. These two neuropeptides seem to be pivotal for the modulation of reproductive activity in response to internal and external cues. It is well-documented that the current metabolic status of the body is closely linked to its reproductive output. However, how reproductive function is regulated by the body's energy status is less clear. Recent studies have suggested an active participation of hypothalamic KP and GnIH in the modulation of reproductive function according to available metabolic cues. Expression of KISS1, the KP encoding gene, is decreased while expression of RFRP (NPVF), the gene encoding GnIH, is increased in metabolic deficiency conditions. The lower levels of KP, as suggested by a decrease in KISS1 gene mRNA expression, during metabolic deficiency can be corrected by administration of exogenous KP, which leads to an increase in reproductive hormone levels. Likewise, administration of RF9, a GnIH receptor antagonist, can reverse the inhibitory effect of fasting on testosterone in monkeys. Together, it is likely that the integrated function of both these hypothalamic neuropeptides works as a reproductive output regulator in response to a change in metabolic status. In this review, we have summarized literature from nonprimate and primate studies that demonstrate the involvement of KP and GnIH in the metabolic regulation of reproduction.

Kisspeptin (KP)-Kiss1r, a ligand-receptor pair, has recently been implicated as a pivotal regulator of the neuroendocrine reproductive axis. KISS1 (encoding KP) as well as KISS1R (encoding receptor for KP) are expressed in several peripheral tissues including the pancreas. But the specific role of KP in the physiology of pancreas is still incompletely deciphered. This study was designed to examine the effect of peripheral KP administration on basal and glucose-induced plasma insulin (an important pancreatic hormone) secretion under fed and fasting conditions in the adult male rhesus monkey. A set of 4 chair-restraint habituated intact adult male rhesus monkeys were assigned to receive intravenous bolus administration of human kisspeptin-10 (KP10, 50 μg), and vehicle (1 ml) in normal fed and fasting conditions without or with glucose infusions. Plasma concentrations of insulin were measured by using a specific IRMA. Glucose infusion significantly stimulated plasma insulin levels (p<0.005). Vehicle administration did not affect both basal and glucose stimulated insulin in fed as well as in fasting condition. KP10 administration had no effect on the basal insulin levels in both fed and fasting as compared to pretreatment or vehicle treatment levels, while it significantly heightened glucose stimulated insulin levels (p<0.05) in both fed and fasted monkeys. The present results show that KP administration does not affect the basal secretion of insulin under both fed and fasting condition while potentiated the glucose-induced insulin levels in the adult male rhesus monkey. Therefore, these findings suggest a potential role of KP in the physiology of pancreas.

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