KiSS‐1 Neurones Are Direct Targets for Leptin in the ob/ob Mouse

Abstract

Leptin is an adipocyte-derived hormone that acts on the hypothalamus to influence feeding, metabolism and reproduction, but the cellular and molecular targets for the action of leptin in the brain have yet to be fully elucidated. Kisspeptins are encoded by the Kiss1 gene, which is expressed in the hypothalamus and has been implicated in the neuroendocrine regulation of gonadotrophin-releasing hormone secretion. We tested the hypothesis that kisspeptin-expressing neurones are targets for leptin. First, we examined whether leptin regulates the expression of Kiss1 by comparing levels of KiSS-1 mRNA in the arcuate nucleus among groups of mice having different circulating levels of leptin: (i) wild-type (WT); (ii) leptin-deficient ob/ob; and (iii) ob/ob mice treated with leptin. All mice were castrated to control for endogenous concentrations of gonadal steroids. KiSS-1 mRNA was significantly reduced in ob/ob compared to WT mice and levels of KiSS-1 mRNA in ob/ob mice treated with leptin were increased, but not fully restored to that found in WT animals. Second, we performed double-label in situ hybridisation for KiSS-1 mRNA and the leptin receptor (Ob-Rb) mRNA and found that almost one-half (approximately 40%) of KiSS-1 mRNA-expressing cells in the arcuate nucleus expressed Ob-Rb mRNA. These results demonstrate that KiSS-1 neurones are direct targets for regulation by leptin and suggest that the reproductive deficits associated with leptin-deficient states may be attributable, in part, to diminished expression of Kiss1.

Kisspeptin signaling in the brain: Recent developments and future challenges

“…Compelling evidence, though, has demonstrated that the adipose hormone, leptin, is a master hormonal regulator of hypothalamic Kiss1, as evidenced by rodent studies, where conditions of hypoleptinemia were linked to decreased hypothalamic expression of Kiss1 mRNA, which could be rescued by central administration of leptin [41,45]. However, some crucial facets of this regulatory pathway remain to be unfolded.…”

Caloric restriction: Impact upon pituitary function and reproduction

“…However, despite this seemingly direct control of GnRH function, it is still unclear whether there is a significant amount of leptin receptor expression in hypothalamic GnRH neurons (Chan and Mantzoros, 2001;Watanobe, 2002). Another possible mechanism by which leptin regulation controls GnRH functionality is through its ability to activate kisspeptinpositive neurons (Smith et al, 2006). Kisspeptin, the gene product of the Kiss-1 gene, binds to and signals through the GPR54 G protein-coupled receptor expressed in high levels in GnRH-positive neurons in the hypothalamus (Irwig et al, 2004;Messager et al, 2005).…”

“…fasting, is associated with an inhibition in the expression of Kiss1 mRNA along with the well-described decreased circulating levels of leptin . Leptin-deficient ob/ob mice have reduced levels of Kiss1 mRNA compared to wildtype controls, and the central administration of leptin partially reduces this effect (Smith et al, 2006). Further support of the notion that the cells are regulated by leptin is the observation that 40% of Kiss1 cells in the arcuate nucleus express the signaling version of the leptin receptor, ObRb (Smith et al, 2006).…”

Effect of Iron Overload on Gonadotrophins and Organ Sex Steroids in Pubertal Thalassemia Patients

“…Moreover, hypogonadotropic hypogonadism in thalassemia is related not only to iron toxicity on gonadotrope cells but also to adipose tissue leptin [31], liver disorders, chronic hypoxia and zinc deficiency which remains unexplored by us. Larger sample size was also required to improve the statistical importance of this study which was also one of our limitations.…”