Regulation of Hypothalamic Expression of KiSS-1 and GPR54 Genes by Metabolic Factors: Analyses Using Mouse Models and a Cell Line

Abstract

It is well established that reproductive function is metabolically gated. However, the mechanisms whereby energy stores and metabolic cues influence fertility are yet to be completely deciphered. Recently, the hypothalamic KiSS-1/GPR54 system has emerged as a fundamental regulator of the gonadotropic axis, which conveys the modulatory actions of sex steroids to GnRH neurons. Evidence is also mounting that KiSS-1 neurons may also represent the link between systemic metabolic signals and central control of reproduction. To further explore this possibility, we examined the impact of changes in energy status and key metabolic regulators on the hypothalamic expression of KiSS-1 and GPR54 genes, using different mouse models and the hypothalamic cell line N6. Time-course analysis of the effects of short-term fasting revealed a rapid (12- and 24-h) decline in KiSS-1 and GPR54 mRNA levels, which preceded that of GnRH (48 h). In contrast, diet-induced obesity or obesity associated with leptin deficiency (ob/ob vs. wild-type mice) failed to induce overt changes in hypothalamic expression of KiSS-1 and GPR54 genes. However, leptin infusion of ob/ob mice evoked a significant increase in KiSS-1 and GPR54 mRNA levels compared with pair-fed controls. Moreover, leptin, but not insulin or IGF-I, stimulated KiSS-1 mRNA expression in the mouse hypothalamic cell line N6. In addition, neuropeptide Y (NPY) null mice showed decreased KiSS-1 mRNA levels at the hypothalamus, whereas exposure to NPY increased expression of KiSS-1 in hypothalamic N6 cells. In sum, our present data further characterize the functional relevance and putative key mediators (such as leptin and NPY) of the metabolic regulation of the hypothalamic KiSS-1 system in the mouse.

Timing and completion of puberty in female mice depend on estrogen receptor α-signaling in kisspeptin neurons

“…PCR reactions were performed with IQ SYBR Green Supermix (BioRad), and fluorescence was measured using the MyiQ quantitative real-time thermocycler (BioRad). The following primer sets were used: Kiss1 (sense 5′-AGCTGCTGCTTCTCCTCTGT-3′ and antisense 5′-GCATACCGCGATTCCTTTT-3′) (44). TaqMan was used to measure GAPDH reference gene levels, and were measured on an IQ5 thermocylcer (BioRad); sense 5′-GGGCATCTTGGGCTA-CACT-3′, antisense 5′-GGCATCGAAGGTGGAAGAGT-3′, probe 5′-Cal fluoro red-610-AGGACCAGGTTGTCTCCTGCGA-BHQ2 3′.…”

Kisspeptin signaling in the brain: Recent developments and future challenges

“…These may include, among others, melatonin, neuropeptide Y and IGF-1 [33][34][35], although their roles in the physiologic control of the KISS1 system in different conditions (from changes in photoperiod to metabolic stress) have not been conclusively defined and merit further investigation. Intriguingly, recent work in sheep has revealed that Kiss1 neurons at the ARC co-express dynorphin (Dyn) and neurokinin-B (NKB) [36], which might operate as A c c e p t e d M a n u s c r i p t Kisspeptin signaling in the brain 7 auto-regulatory signals for kisspeptin neurons in the mouse also.…”

“…In recent years, the metabolic regulation of the hypothalamic KISS1 system has been exposed, mainly by experimental studies in rodents, where conditions of negative energy balance were shown to induce variable degrees of inhibition of Kiss1 mRNA expression [34,[40][41][42][43]. These analyses, together with the rescue of gonadotropic function by exogenous kisspeptin in these conditions, have allowed us to suggest that kisspeptin neurons at the hypothalamus operate as sensor and neuroendocrine conduit for conveying metabolic information onto brain reproductive centers (likely, GnRH neurons), thereby contributing to the well-known coupling between body energy status, puberty onset and fertility [42,44].…”

Recent advances in reproductive neuroendocrinology: a role for RFamide peptides in seasonal reproduction?

“…fasting) or signals of energy availability (e.g. leptin; Castellano et al 2005Castellano et al , 2006bSmith et al 2006;Luque et al 2007). Recent evidence suggests that GnIH may interact with the ingestive system in chickens and rats, with injections of GnIH leading to a significant increase in feeding behaviour (Tachibana et al 2005;Johnson et al 2007).…”