Background:Kisspeptins, encoded byKiss1, have emerged as essential regulators of puberty and reproduction byprimarily acting on GnRH neurons, via their canonical receptor, Gpr54. Mounting, as yet fragmentary, evidencestrongly suggests that kisspeptin signaling may also participate in the control of key aspects of body energyand metabolic homeostasis. However, characterization of such metabolic dimension of kisspeptins remainsuncomplete, without an unambiguous discrimination between the primary metabolic actions of kisspeptins vs.those derived from their ability to stimulate the secretion of gonadal hormones, which have distinct metabolicactions on their own.Inthis work,weaimed to tease apart primaryvs. secondaryeffects ofkisspeptins in the con-trol of key aspects of metabolic homeostasis using genetic models of impaired kisspeptin signaling and/or go-nadal hormone status.Methods:Body weight (BW) gain and composition, food intake and key metabolic parameters, including glucosetolerance, were comparatively analyzed, in lean and obesogenic conditions, in mice lacking kisspeptin signalingdue to global inactivation of Gpr54 (displaying profound hypogonadism; Gpr54−/−) vs. Gpr54 null mice with se-lective re-introduction of Gpr54 expression only in GnRH cells (Gpr54−/−Tg), where kisspeptin signaling else-where than in GnRH neurons is ablated but gonadal function is preserved.Results:In male mice, global elimination of kisspeptin signaling resulted in decreased BW, feeding suppressionand increased adiposity, without overt changes in glucose tolerance, whereas Gpr54−/−female mice displayedenhanced BW gain at adulthood, increased adiposity and perturbed glucose tolerance, despite reduced food in-take. Gpr54−/−Tg rescued mice showed altered postnatal BW gain in males and mildly perturbed glucose toler-ance in females, with intermediate phenotypes between control and global KO animals. Yet, body compositionand leptin levels were similar to controls in gonadal-rescued mice. Exposure to obesogenic insults, such ashigh fat diet (HFD), resulted in exaggerated BW gain and adiposity in global Gpr54−/−mice of both sexes, andworsening of glucose tolerance, especially in females. Yet, while rescued Gpr54−/−Tg males displayed interme-diate BW gain and feeding profiles and impaired glucose tolerance,rescued Gpr54−/−Tg females behaved as con-trols, except for a modest deterioration of glucose tolerance after ovariectomy.Conclusion:Our data support a global role of kisspeptin signaling in the control of body weight and metabolic ho-meostasis, with a dominant contribution of gonadal hormone-dependent actions. However, our results docu-ment also discernible primary effects of kisspeptin signaling in the regulation of body weight gain, feeding andresponses to obesogenic insults, which occur in a sexually-dimorphic manner.Summary of translational relevance:Kisspeptins, master regulators of reproduction, may also participate in thecontrol of key aspects of body energy and metabolic homeostasis; yet, the nature of such metabolic actions re-mains debatable, due in part to the fact that kisspeptins modulate gonadal hormones, which have metabolic
actions on their own. By comparing the metabolic profiles of two mouse models with genetic inactivation ofkisspeptin signaling but different gonadal status (hypogonadal vs. preserved gonadal function), we provideherein a systematic dissection of gonadal-dependent vs. -independent metabolic actions of kisspeptins. Ourdata support a global role of kisspeptin signaling in the control of body weight and metabolic homeostasis,with a dominant contribution of gonadal hormone-dependent actions. However, our results document also dis-cernible primary effects of kisspeptin signaling in the regulation of body weight gain, feeding and responses toobesogenic insults, which occur in a sexually-dimorphic manner. These data pave the way for future analyses ad-dressingtheeventualcontribution ofalteredkisspeptinsignaling inthedevelopmentof metabolic alterations, es-pecially in conditions linked to reproductive dysfunction.