title: The Brain-to-Pancreatic Islet Neuronal Map Reveals Differential Glucose Regulation From Distinct Hypothalamic Regions.
abstract: The brain influences glucose homeostasis, partly by supplemental control over insulin and glucagon secretion. Without this central regulation, diabetes and its complications can ensue. Yet, the neuronal network linking to pancreatic islets has never been fully mapped. Here, we refine this map using pseudorabies virus (PRV) retrograde tracing, indicating that the pancreatic islets are innervated by efferent circuits that emanate from the hypothalamus. We found that the hypothalamic arcuate nucleus (ARC), ventromedial nucleus (VMN), and lateral hypothalamic area (LHA) significantly overlap PRV and the physiological glucose-sensing enzyme glucokinase. Then, experimentally lowering glucose sensing, specifically in the ARC, resulted in glucose intolerance due to deficient insulin secretion and no significant effect in the VMN, but in the LHA it resulted in a lowering of the glucose threshold that improved glucose tolerance and/or improved insulin sensitivity, with an exaggerated counter-regulatory response for glucagon secretion. No significant effect on insulin sensitivity or metabolic homeostasis was noted. Thus, these data reveal novel direct neuronal effects on pancreatic islets and also render a functional validation of the brain-to-islet neuronal map. They also demonstrate that distinct regions of the hypothalamus differentially control insulin and glucagon secretion, potentially in partnership to help maintain glucose homeostasis and guard against hypoglycemia.
authors.affiliation: Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL.
authors.forename: Wilfredo
authors.initials: W
authors.lastname: Rosario
authors.affiliation: Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL.
authors.forename: Inderroop
authors.initials: I
authors.lastname: Singh
authors.affiliation: Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Wautlet
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI.
authors.forename: Christa
authors.initials: C
authors.lastname: Patterson
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Flak
authors.affiliation: Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, NC.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Becker
authors.affiliation: Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL.
authors.forename: Almas
authors.initials: A
authors.lastname: Ali
authors.affiliation: Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tamarina
authors.affiliation: Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL.
authors.forename: Louis H
authors.initials: LH
authors.lastname: Philipson
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ.
authors.forename: Lynn W
authors.initials: LW
authors.lastname: Enquist
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
authors.affiliation: Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL cjrhodes@uchicago.edu.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rhodes
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D001931:Brain Mapping; D005260:Female; D005941:Glucokinase / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007026:Hypothalamic Area, Lateral / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000294:innervation / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D014697:Ventromedial Hypothalamic Nucleus / Q000378:metabolism
chemical_list: D005941:Glucokinase; D005947:Glucose