title: AgRP to Kiss1 neuron signaling links nutritional state and fertility.
abstract: Mammalian reproductive function depends upon a neuroendocrine circuit that evokes the pulsatile release of gonadotropin hormones (luteinizing hormone and follicle-stimulating hormone) from the pituitary. This reproductive circuit is sensitive to metabolic perturbations. When challenged with starvation, insufficient energy reserves attenuate gonadotropin release, leading to infertility. The reproductive neuroendocrine circuit is well established, composed of two populations of kisspeptin-expressing neurons (located in the anteroventral periventricular hypothalamus, Kiss1AVPV, and arcuate hypothalamus, Kiss1ARH), which drive the pulsatile activity of gonadotropin-releasing hormone (GnRH) neurons. The reproductive axis is primarily regulated by gonadal steroid and circadian cues, but the starvation-sensitive input that inhibits this circuit during negative energy balance remains controversial. Agouti-related peptide (AgRP)-expressing neurons are activated during starvation and have been implicated in leptin-associated infertility. To test whether these neurons relay information to the reproductive circuit, we used AgRP-neuron ablation and optogenetics to explore connectivity in acute slice preparations. Stimulation of AgRP fibers revealed direct, inhibitory synaptic connections with Kiss1ARHand Kiss1AVPVneurons. In agreement with this finding, Kiss1ARHneurons received less presynaptic inhibition in the absence of AgRP neurons (neonatal toxin-induced ablation). To determine whether enhancing the activity of AgRP neurons is sufficient to attenuate fertility in vivo, we artificially activated them over a sustained period and monitored fertility. Chemogenetic activation with clozapine N-oxide resulted in delayed estrous cycles and decreased fertility. These findings are consistent with the idea that, during metabolic deficiency, AgRP signaling contributes to infertility by inhibiting Kiss1 neurons.
authors.affiliation: Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Padilla
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97239.
authors.forename: Jian
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97239.
authors.forename: Casey C
authors.initials: CC
authors.lastname: Nestor
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97239.
authors.forename: Chunguang
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97239.
authors.forename: Arik W
authors.initials: AW
authors.lastname: Smith
authors.affiliation: Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Whiddon
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97239.|Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006.
authors.forename: Oline K
authors.initials: OK
authors.lastname: Rønnekleiv
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97239.|Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Kelly
authors.affiliation: Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195; palmiter@uw.edu.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Palmiter
mesh_terms: D054369:Agouti-Related Protein / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D057906:Circadian Clocks / Q000187:drug effects / Q000502:physiology; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D030762:Estrous Cycle / Q000187:drug effects / Q000502:physiology; D005260:Female; D005298:Fertility / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D059648:Kisspeptins / Q000235:genetics* / Q000378:metabolism; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D007986:Luteinizing Hormone / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D062308:Optogenetics; D012098:Reproduction / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction; D013217:Starvation / Q000235:genetics*; D013238:Stereotaxic Techniques
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; C491407:Kiss1 protein, mouse; D059648:Kisspeptins; D020738:Leptin; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D003024:Clozapine; C079149:clozapine N-oxide
keywords: agouti-related peptide; fertility; gonadotrophin-releasing hormone; kisspeptin; leptin