title: Leptin deficiency and diet-induced obesity reduce hypothalamic kisspeptin expression in mice.
abstract: The hormone leptin modulates a diverse range of biological functions, including energy homeostasis and reproduction. Leptin promotes GnRH function via an indirect action on forebrain neurons. We tested whether leptin deficiency or leptin resistance due to a high-fat diet (HFD) can regulate the potent reproductive neuropeptide kisspeptin. In mice with normalized levels of estradiol, leptin deficiency markedly reduced kisspeptin gene expression, particularly in the arcuate nucleus (ARC), and kisspeptin immunoreactive cell numbers in the rostral periventricular region of the third ventricle (RP3V). The HFD model was used to determine the effects of diet-induced obesity and central leptin resistance on kisspeptin cell number and gene expression. DBA/2J mice, which are prone to HFD-induced infertility, showed a marked decrease in kisspeptin expression in both the RP3V and ARC and cell numbers in the RP3V after HFD. This is the first evidence that kisspeptin can be regulated by HFD and/or increased body weight. Next we demonstrated that leptin does not signal (via signal transducer and activator of transcription 3 or 5, or mammalian target of rapamycin) directly on kisspeptin-expressing neurons in the RP3V. Lastly, in leptin receptor-deficient mice, neither GnRH nor kisspeptin neurons were activated during a preovulatory-like GnRH/LH surge induction regime, indicating that leptin's actions on GnRH may be upstream of kisspeptin neurons. These data provide evidence that leptin's effects on reproductive function are regulated by kisspeptin neurons in both the ARC and RP3V, although in the latter site the effects are likely to be indirect.
authors.affiliation: Centre for Neuroendocrinology and Department of Anatomy and Structural Biology, University of Otago School of Medical Sciences, PO Box 913, Dunedin 9054, New Zealand. janette.quennell@anatomy.otago.ac.nz
authors.forename: Janette H
authors.initials: JH
authors.lastname: Quennell
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Howell
authors.forename: Juan
authors.initials: J
authors.lastname: Roa
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Augustine
authors.forename: David R
authors.initials: DR
authors.lastname: Grattan
authors.forename: Greg M
authors.initials: GM
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001835:Body Weight / Q000502:physiology; D004041:Dietary Fats / Q000009:adverse effects*; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000097:blood; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D007150:Immunohistochemistry; D059648:Kisspeptins; D020738:Leptin / Q000097:blood* / Q000172:deficiency; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011863:Radioimmunoassay; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; C491407:Kiss1 protein, mouse; D059648:Kisspeptins; D020738:Leptin; D011506:Proteins; D025521:Tumor Suppressor Proteins; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol