title: A parabrachial-hypothalamic cholecystokinin neurocircuit controls counterregulatory responses to hypoglycemia.
abstract: Hypoglycemia engenders an autonomically mediated counterregulatory (CR)-response that stimulates endogenous glucose production to maintain concentrations within an appropriate physiological range. Although the involvement of the brain in preserving normoglycemia has been established, the neurocircuitry underlying centrally mediated CR-responses remains unclear. Here we demonstrate that lateral parabrachial nucleus cholecystokinin (CCK(LPBN)) neurons are a population of glucose-sensing cells (glucose inhibited) with counterregulatory capacity. Furthermore, we reveal that steroidogenic-factor 1 (SF1)-expressing neurons of the ventromedial nucleus of the hypothalamus (SF1(VMH)) are the specific target of CCK(LPBN) glucoregulatory neurons. This discrete CCK(LPBN)→SF1(VMH) neurocircuit is both necessary and sufficient for the induction of CR-responses. Together, these data identify CCK(LPBN) neurons, and specifically CCK neuropeptide, as glucoregulatory and provide significant insight into the homeostatic mechanisms controlling CR-responses to hypoglycemia.
authors.affiliation: Centre for Integrative Physiology, Hugh Robson Building, University of Edinburgh, Edinburgh, EH8 9XD, UK; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: agarfiel@bidmc.harvard.edu.
authors.forename: Alastair S
authors.initials: AS
authors.lastname: Garfield
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Bhavik P
authors.initials: BP
authors.lastname: Shah
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Madara
authors.affiliation: Department of Medicine and Wellcome Trust/Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK; Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
authors.forename: Luke K
authors.initials: LK
authors.lastname: Burke
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48105, USA.
authors.forename: Christa M
authors.initials: CM
authors.lastname: Patterson
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48105, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Flak
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.affiliation: Department of Medicine and Wellcome Trust/Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Evans
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Lowell
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48105, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
authors.forename: Lora K
authors.initials: LK
authors.lastname: Heisler
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002766:Cholecystokinin / Q000378:metabolism*; D007003:Hypoglycemia / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D051379:Mice; D065823:Parabrachial Nucleus / Q000166:cytology
chemical_list: D001786:Blood Glucose; D002766:Cholecystokinin