title: Insulin and Leptin Signaling Interact in the Mouse Kiss1 Neuron during the Peripubertal Period.
abstract: Reproduction requires adequate energy stores for parents and offspring to survive. Kiss1 neurons, which are essential for fertility, have the potential to serve as the central sensors of metabolic factors that signal to the reproductive axis the presence of stored calories. Paradoxically, obesity is often accompanied by infertility. Despite excess circulating levels of insulin and leptin, obese individuals exhibit resistance to both metabolic factors in many neuron types. Thus, resistance to insulin or leptin in Kiss1 neurons could lead to infertility. Single deletion of the receptors for either insulin or the adipokine leptin from Kiss1 neurons does not impair adult reproductive dysfunction. However, insulin and leptin signaling pathways may interact in such a way as to obscure their individual functions. We hypothesized that in the presence of genetic or obesity-induced concurrent insulin and leptin resistance, Kiss1 neurons would be unable to maintain reproductive function. We therefore induced a chronic hyperinsulinemic and hyperleptinemic state in mice lacking insulin receptors in Kiss1 neurons through high fat feeding and examined the impact on fertility. In an additional, genetic model, we ablated both leptin and insulin signaling in Kiss1 neurons (IR/LepRKiss mice). Counter to our hypothesis, we found that the addition of leptin insensitivity did not alter the reproductive phenotype of IRKiss mice. We also found that weight gain, body composition, glucose and insulin tolerance were normal in mice of both genders. Nonetheless, leptin and insulin receptor deletion altered pubertal timing as well as LH and FSH levels in mid-puberty in a reciprocal manner. Our results confirm that Kiss1 neurons do not directly mediate the critical role that insulin and leptin play in reproduction. However, during puberty kisspeptin neurons may experience a critical window of susceptibility to the influence of metabolic factors that can modify the onset of fertility.
authors.affiliation: Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, New York, United States of America.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Bioengineering, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Hoangha
authors.initials: H
authors.lastname: Dao
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, United States of America.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Wang
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, United States of America.
authors.forename: Amelia
authors.initials: A
authors.lastname: Heston
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, United States of America.
authors.forename: Kaitlyn M
authors.initials: KM
authors.lastname: Garcia
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, United States of America.
authors.forename: Alisha
authors.initials: A
authors.lastname: Sangal
authors.affiliation: Center for Reproductive Genomics, Cornell University, Ithaca, NY, United States of America.
authors.forename: Abigail R
authors.initials: AR
authors.lastname: Dowling
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, United States of America.
authors.forename: Latrice D
authors.initials: LD
authors.lastname: Faulkner
authors.affiliation: Department of Bioengineering, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Molitor
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States of America.
authors.forename: Carol F
authors.initials: CF
authors.lastname: Elias
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, United States of America; Department of Obstetrics-Gynecology, University of Toledo College of Medicine, Toledo, Ohio, United States of America.
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Hill
mesh_terms: D000818:Animals; D005260:Female; D005298:Fertility; D007328:Insulin / Q000378:metabolism*; D059648:Kisspeptins / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D011627:Puberty / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D012741:Sexual Maturation; D015398:Signal Transduction
chemical_list: D007328:Insulin; C491407:Kiss1 protein, mouse; D059648:Kisspeptins; D020738:Leptin; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D011972:Receptor, Insulin