Leptin is not the Critical Signal for Kisspeptin or Luteinising Hormone Restoration During Exit from Negative Energy Balance

Abstract

Low levels of the adipocyte hormone leptin are considered to be the key signal contributing to inhibited gonadotrophin-releasing hormone (GnRH) release and reproductive acyclicity during negative energy balance. Hypoleptinaemia-induced inhibition of GnRH may be initiated with upstream inhibition of the secretagogue kisspeptin (Kiss1) because GnRH neurones do not express leptin receptors. The present study aimed to determine whether eliminating the hypoleptinaemia associated with caloric restriction (CR), by restoring leptin to normal basal levels, could reverse the suppression of the reproductive neuroendocrine axis. Fifty percent CR resulted in significant suppression of anteroventral periventricular Kiss1 mRNA, arcuate nucleus (ARH) Kiss1 and neurokinin B (NKB) mRNA levels and serum luteinising hormone (LH). Restoring leptin to normal basal levels did not restore Kiss1 or NKB mRNA or LH levels. Surprisingly, leptin did not activate expression of phosphorylated signal-transducer and activator of transcription-3 in ARC Kiss1 neurones, indicating that these neurones may not relay leptin signalling to GnRH neurones. Previous work in fasting models showing restoration of LH used a pharmacological dose of leptin. Therefore, in a 48-h fast study, replacement of leptin to pharmacological levels was compared with replacement of leptin to normal basal levels. Maintaining leptin at normal basal levels during the fast did not prevent inhibition of LH. By contrast, pharmacological levels of leptin did maintain LH at control values. These results suggest that, although leptin may be a permissive signal for reproductive function, hypoleptinaemia is unlikely to be the critical signal responsible for ARC Kiss1 and LH inhibition during negative energy balance.

AgRP to Kiss1 neuron signaling links nutritional state and fertility

“…Mice that cannot make leptin (Lep ob/ob ) or respond to it (Lepr db/db ) are infertile (32, 33) and leptin levels fall with the loss of adipose tissue during starvation (1,(34)(35)(36). Both AgRP and Kiss1 neurons are leptin sensitive (37); however, genetic loss of leptin signaling in either of these populations does not affect fertility (38,39) and restoration of leptin in calorically restricted rodents does not restore reproduction (40). A critical experiment is to determine whether leptin signaling only in AgRP neurons is sufficient to maintain fertility in Lep db/db mice.…”

Kisspeptin and energy balance in reproduction

“…Similarly, restoration of leptin to normal basal levels in caloric restricted female rats does not restore Kiss1 mRNA or plasma LH levels (True et al 2011). Although it could be argued in the latter that a required threshold of leptin was not reached because higher 'pharmacological' levels of leptin replacement in this study did maintain LH at control values (True et al 2011). Nevertheless, alternative regulators of metabolism are very likely involved in kisspeptin regulation and should be explored.…”

“…In sheep, the restoration of ad libitum feeding in food-restricted ewes rescues pulsatile LH secretion but does so prior to any change in circulating leptin concentrations (Szymanski et al 2007). Similarly, restoration of leptin to normal basal levels in caloric restricted female rats does not restore Kiss1 mRNA or plasma LH levels (True et al 2011). Although it could be argued in the latter that a required threshold of leptin was not reached because higher 'pharmacological' levels of leptin replacement in this study did maintain LH at control values (True et al 2011).…”

Energy status and ovarian follicular development

“…Furthermore, in Syrian hamsters, fasting-induced anestrous can be reversed by leptin treatment, but not when the availability of oxidizable metabolic fuels is blocked by the use of pharmacological inhibitors of glucose and fatty acid oxidation [85,86]. In line with this study, in rats, pulsatile LH secretion is inhibited by fasting or treatment with inhibitors of glucose or fatty acid oxidation [87,88]. Control of reproductive processes by the availability of oxidizable metabolic fuels has been documented in other model systems as well [89][90][91][92][93].…”

“…The absence of FSH in the culture medium increases the production of reactive oxygen species (ROS) prior to any morphological or physiological indications of apoptosis, while FSH supplementation suppresses ROS production in the cultured large antral follicles [82,86]. Furthermore, FSH treatment of female rats has been shown to enhance the expression of antioxidant genes, such as superoxide dismutase 2 [87]. In vitro exposure of goat granulosa cells to FSH has been shown to lead to increased activity of the antioxidant enzyme catalase [88], while FSH treatment in rats results in enhanced ovarian synthesis of the antioxidant glutathione (GSH) [89].…”