title: Intracerebroventricular Catalase Reduces Hepatic Insulin Sensitivity and Increases Responses to Hypoglycemia in Rats.
abstract: Specialized metabolic sensors in the hypothalamus regulate blood glucose levels by influencing hepatic glucose output and hypoglycemic counterregulatory responses. Hypothalamic reactive oxygen species (ROS) may act as a metabolic signal-mediating responses to changes in glucose, other substrates and hormones. The role of ROS in the brain's control of glucose homeostasis remains unclear. We hypothesized that hydrogen peroxide (H2O2), a relatively stable form of ROS, acts as a sensor of neuronal glucose consumption and availability and that lowering brain H2O2with the enzyme catalase would lead to systemic responses increasing blood glucose. During hyperinsulinemic euglycemic clamps in rats, intracerebroventricular catalase infusion resulted in increased hepatic glucose output, which was associated with reduced neuronal activity in the arcuate nucleus of the hypothalamus. Electrophysiological recordings revealed a subset of arcuate nucleus neurons expressing proopiomelanocortin that were inhibited by catalase and excited by H2O2. During hypoglycemic clamps, intracerebroventricular catalase increased glucagon and epinephrine responses to hypoglycemia, consistent with perceived lower glucose levels. Our data suggest that H2O2represents an important metabolic cue, which, through tuning the electrical activity of key neuronal populations such as proopiomelanocortin neurons, may have a role in the brain's influence of glucose homeostasis and energy balance.
authors.affiliation: Wellcome Trust/Medical Research Council Institute of Metabolic Science and Department of Medicine (S.P.M., C.-Y.Y., C.R., P.H., M.L.E.), University of Cambridge, Cambridge CB20QQ, United Kingdom; Rowett Institute of Nutrition and Health (D.L., L.K.H.), University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom; Department of Family Medicine (C.-Y.Y.), Chang Gung Memorial Hospital, Chiayi, Taiwan; Chang Gung University of Science and Technology (C.-Y.Y.), Taoyuan City 33303, Taiwan; Oxford Centre for Diabetes, Endocrinology and Metabolism (B.F.), University of Oxford, Oxford OX37JT, United Kingdom; and Department of Nutritional Sciences (B.F.), University of Surrey, Guildford GU27XH, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Pauliina Markkula
authors.affiliation: Wellcome Trust/Medical Research Council Institute of Metabolic Science and Department of Medicine (S.P.M., C.-Y.Y., C.R., P.H., M.L.E.), University of Cambridge, Cambridge CB20QQ, United Kingdom; Rowett Institute of Nutrition and Health (D.L., L.K.H.), University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom; Department of Family Medicine (C.-Y.Y.), Chang Gung Memorial Hospital, Chiayi, Taiwan; Chang Gung University of Science and Technology (C.-Y.Y.), Taoyuan City 33303, Taiwan; Oxford Centre for Diabetes, Endocrinology and Metabolism (B.F.), University of Oxford, Oxford OX37JT, United Kingdom; and Department of Nutritional Sciences (B.F.), University of Surrey, Guildford GU27XH, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Lyons
authors.affiliation: Wellcome Trust/Medical Research Council Institute of Metabolic Science and Department of Medicine (S.P.M., C.-Y.Y., C.R., P.H., M.L.E.), University of Cambridge, Cambridge CB20QQ, United Kingdom; Rowett Institute of Nutrition and Health (D.L., L.K.H.), University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom; Department of Family Medicine (C.-Y.Y.), Chang Gung Memorial Hospital, Chiayi, Taiwan; Chang Gung University of Science and Technology (C.-Y.Y.), Taoyuan City 33303, Taiwan; Oxford Centre for Diabetes, Endocrinology and Metabolism (B.F.), University of Oxford, Oxford OX37JT, United Kingdom; and Department of Nutritional Sciences (B.F.), University of Surrey, Guildford GU27XH, United Kingdom.
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Yueh
authors.affiliation: Wellcome Trust/Medical Research Council Institute of Metabolic Science and Department of Medicine (S.P.M., C.-Y.Y., C.R., P.H., M.L.E.), University of Cambridge, Cambridge CB20QQ, United Kingdom; Rowett Institute of Nutrition and Health (D.L., L.K.H.), University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom; Department of Family Medicine (C.-Y.Y.), Chang Gung Memorial Hospital, Chiayi, Taiwan; Chang Gung University of Science and Technology (C.-Y.Y.), Taoyuan City 33303, Taiwan; Oxford Centre for Diabetes, Endocrinology and Metabolism (B.F.), University of Oxford, Oxford OX37JT, United Kingdom; and Department of Nutritional Sciences (B.F.), University of Surrey, Guildford GU27XH, United Kingdom.
authors.forename: Christine
authors.initials: C
authors.lastname: Riches
authors.affiliation: Wellcome Trust/Medical Research Council Institute of Metabolic Science and Department of Medicine (S.P.M., C.-Y.Y., C.R., P.H., M.L.E.), University of Cambridge, Cambridge CB20QQ, United Kingdom; Rowett Institute of Nutrition and Health (D.L., L.K.H.), University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom; Department of Family Medicine (C.-Y.Y.), Chang Gung Memorial Hospital, Chiayi, Taiwan; Chang Gung University of Science and Technology (C.-Y.Y.), Taoyuan City 33303, Taiwan; Oxford Centre for Diabetes, Endocrinology and Metabolism (B.F.), University of Oxford, Oxford OX37JT, United Kingdom; and Department of Nutritional Sciences (B.F.), University of Surrey, Guildford GU27XH, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Hurst
authors.affiliation: Wellcome Trust/Medical Research Council Institute of Metabolic Science and Department of Medicine (S.P.M., C.-Y.Y., C.R., P.H., M.L.E.), University of Cambridge, Cambridge CB20QQ, United Kingdom; Rowett Institute of Nutrition and Health (D.L., L.K.H.), University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom; Department of Family Medicine (C.-Y.Y.), Chang Gung Memorial Hospital, Chiayi, Taiwan; Chang Gung University of Science and Technology (C.-Y.Y.), Taoyuan City 33303, Taiwan; Oxford Centre for Diabetes, Endocrinology and Metabolism (B.F.), University of Oxford, Oxford OX37JT, United Kingdom; and Department of Nutritional Sciences (B.F.), University of Surrey, Guildford GU27XH, United Kingdom.
authors.forename: Barbara
authors.initials: B
authors.lastname: Fielding
authors.affiliation: Wellcome Trust/Medical Research Council Institute of Metabolic Science and Department of Medicine (S.P.M., C.-Y.Y., C.R., P.H., M.L.E.), University of Cambridge, Cambridge CB20QQ, United Kingdom; Rowett Institute of Nutrition and Health (D.L., L.K.H.), University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom; Department of Family Medicine (C.-Y.Y.), Chang Gung Memorial Hospital, Chiayi, Taiwan; Chang Gung University of Science and Technology (C.-Y.Y.), Taoyuan City 33303, Taiwan; Oxford Centre for Diabetes, Endocrinology and Metabolism (B.F.), University of Oxford, Oxford OX37JT, United Kingdom; and Department of Nutritional Sciences (B.F.), University of Surrey, Guildford GU27XH, United Kingdom.
authors.forename: Lora K
authors.initials: LK
authors.lastname: Heisler
authors.affiliation: Wellcome Trust/Medical Research Council Institute of Metabolic Science and Department of Medicine (S.P.M., C.-Y.Y., C.R., P.H., M.L.E.), University of Cambridge, Cambridge CB20QQ, United Kingdom; Rowett Institute of Nutrition and Health (D.L., L.K.H.), University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom; Department of Family Medicine (C.-Y.Y.), Chang Gung Memorial Hospital, Chiayi, Taiwan; Chang Gung University of Science and Technology (C.-Y.Y.), Taoyuan City 33303, Taiwan; Oxford Centre for Diabetes, Endocrinology and Metabolism (B.F.), University of Oxford, Oxford OX37JT, United Kingdom; and Department of Nutritional Sciences (B.F.), University of Surrey, Guildford GU27XH, United Kingdom.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Evans
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism*; D002374:Catalase / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D015309:Glucose Clamp Technique; D006706:Homeostasis / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D007003:Hypoglycemia / Q000378:metabolism*; D057967:Infusions, Intraventricular; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D002374:Catalase