title: CRFR1 in AgRP Neurons Modulates Sympathetic Nervous System Activity to Adapt to Cold Stress and Fasting.
abstract: Signaling by the corticotropin-releasing factor receptor type 1 (CRFR1) plays an important role in mediating the autonomic response to stressful challenges. Multiple hypothalamic nuclei regulate sympathetic outflow. Although CRFR1 is highly expressed in the arcuate nucleus (Arc) of the hypothalamus, the identity of these neurons and the role of CRFR1 here are presently unknown. Our studies show that nearly half of Arc-CRFR1 neurons coexpress agouti-related peptide (AgRP), half of which originate from POMC precursors. Arc-CRFR1 neurons are innervated by CRF neurons in the hypothalamic paraventricular nucleus, and CRF application decreases AgRP(+)CRFR1(+) neurons' excitability. Despite similar anatomy in both sexes, only female mice selectively lacking CRFR1 in AgRP neurons showed a maladaptive thermogenic response to cold and reduced hepatic glucose production during fasting. Thus, CRFR1, in a subset of AgRP neurons, plays a regulatory role that enables appropriate sympathetic nervous system activation and consequently protects the organism from hypothermia and hypoglycemia.
authors.affiliation: Department of Veterinary Resources, Weizmann Institute of Science, 76100 Rehovot, Israel. Electronic address: yael.kuperman@weizmann.ac.il.
authors.forename: Yael
authors.initials: Y
authors.lastname: Kuperman
authors.affiliation: Department of Neurobiology, The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Weizmann Institute of Science, 76100 Rehovot, Israel; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Meira
authors.initials: M
authors.lastname: Weiss
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Julien
authors.initials: J
authors.lastname: Dine
authors.affiliation: Department of Neurobiology, The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Weizmann Institute of Science, 76100 Rehovot, Israel; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Katy
authors.initials: K
authors.lastname: Staikin
authors.affiliation: Biological Services Unit, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Ofra
authors.initials: O
authors.lastname: Golani
authors.affiliation: Department of Neurobiology, The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Weizmann Institute of Science, 76100 Rehovot, Israel; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Assaf
authors.initials: A
authors.lastname: Ramot
authors.affiliation: Department of Neurobiology, The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Tali
authors.initials: T
authors.lastname: Nahum
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kühne
authors.affiliation: Department of Neurobiology, The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Weizmann Institute of Science, 76100 Rehovot, Israel; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Yair
authors.initials: Y
authors.lastname: Shemesh
authors.affiliation: Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Developmental Genetics, 85764 Neuherberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.affiliation: Department of Veterinary Resources, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Harmelin
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Deussing
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eder
authors.affiliation: Department of Neurobiology, The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Weizmann Institute of Science, 76100 Rehovot, Israel; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany. Electronic address: alon.chen@weizmann.ac.il.
authors.forename: Alon
authors.initials: A
authors.lastname: Chen
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D054369:Agouti-Related Protein / Q000378:metabolism*; D000818:Animals; D003080:Cold Temperature; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D005215:Fasting / Q000502:physiology; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000378:metabolism; D006358:Hot Temperature; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*; D022722:Thermogenesis / Q000187:drug effects; D000099052:CRF Receptor, Type 1
chemical_list: D054369:Agouti-Related Protein; D020738:Leptin; D018019:Receptors, Corticotropin-Releasing Hormone; D050796:STAT3 Transcription Factor; D000099052:CRF Receptor, Type 1; D011333:Pro-Opiomelanocortin; D003346:Corticotropin-Releasing Hormone; D005947:Glucose