Intracerebroventricular Catalase Reduces Hepatic Insulin Sensitivity and Increases Responses to Hypoglycemia in Rats

S Pauliina Markkula, David Lyons, Chen-Yu Yueh, Christine Riches, Paul Hurst, Barbara Fielding, Lora K Heisler, Mark L Evans

Research output: Contribution to journalArticle

3 Citations (Scopus)
3 Downloads (Pure)

Abstract

Specialized metabolic-sensors in the hypothalamus regulate blood glucose levels by influencing hepatic glucose output and hypoglycemic counter regulatory 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 H2O2 with the enzyme catalase would lead to systemic responses increasing blood glucose. During hyperinsulinemic euglycemic clamps in rats, ICV catalase infusion resulted in increased hepatic glucose output, which was associated with reduced neuronal activity in the arcuate nucleus of the hypothalamus (ARC). Electrophysiological recordings revealed a subset of ARC neurons expressing pro-opiomelanocortin (POMC) that were inhibited by catalase and excited by H2O2. During hypoglycemic clamps, ICV catalase increased glucagon and epinephrine responses to hypoglycemia, consistent with perceived lower glucose levels. Our data suggest that H2O2 represents an important metabolic cue which, through tuning the electrical activity of key neuronal populations such as POMC neurons, may have a role in the brain's influence of glucose homeostasis and energy balance.

Original languageEnglish
Pages (from-to)4669–4676
Number of pages8
JournalEndocrinology
Volume157
Issue number12
DOIs
Publication statusPublished - 14 Oct 2016

Fingerprint

Hypoglycemia
Catalase
Insulin Resistance
Glucose
Liver
AIDS-Related Complex
Reactive Oxygen Species
Pro-Opiomelanocortin
Hypoglycemic Agents
Blood Glucose
Brain
Homeostasis
Neurons
Arcuate Nucleus of Hypothalamus
Glucose Clamp Technique
Glucagon
Hydrogen Peroxide
Epinephrine
Hypothalamus
Cues

Cite this

Markkula, S. P., Lyons, D., Yueh, C-Y., Riches, C., Hurst, P., Fielding, B., ... Evans, M. L. (2016). Intracerebroventricular Catalase Reduces Hepatic Insulin Sensitivity and Increases Responses to Hypoglycemia in Rats. Endocrinology, 157(12), 4669–4676. https://doi.org/10.1210/en.2015-2054

Intracerebroventricular Catalase Reduces Hepatic Insulin Sensitivity and Increases Responses to Hypoglycemia in Rats. / Markkula, S Pauliina; Lyons, David; Yueh, Chen-Yu; Riches, Christine; Hurst, Paul; Fielding, Barbara; Heisler, Lora K; Evans, Mark L.

In: Endocrinology, Vol. 157, No. 12, 14.10.2016, p. 4669–4676.

Research output: Contribution to journalArticle

Markkula, SP, Lyons, D, Yueh, C-Y, Riches, C, Hurst, P, Fielding, B, Heisler, LK & Evans, ML 2016, 'Intracerebroventricular Catalase Reduces Hepatic Insulin Sensitivity and Increases Responses to Hypoglycemia in Rats', Endocrinology, vol. 157, no. 12, pp. 4669–4676. https://doi.org/10.1210/en.2015-2054
Markkula, S Pauliina ; Lyons, David ; Yueh, Chen-Yu ; Riches, Christine ; Hurst, Paul ; Fielding, Barbara ; Heisler, Lora K ; Evans, Mark L. / Intracerebroventricular Catalase Reduces Hepatic Insulin Sensitivity and Increases Responses to Hypoglycemia in Rats. In: Endocrinology. 2016 ; Vol. 157, No. 12. pp. 4669–4676.
@article{37b84124fb2c4424bd851ac3a1bb1b7f,
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 counter regulatory 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 H2O2 with the enzyme catalase would lead to systemic responses increasing blood glucose. During hyperinsulinemic euglycemic clamps in rats, ICV catalase infusion resulted in increased hepatic glucose output, which was associated with reduced neuronal activity in the arcuate nucleus of the hypothalamus (ARC). Electrophysiological recordings revealed a subset of ARC neurons expressing pro-opiomelanocortin (POMC) that were inhibited by catalase and excited by H2O2. During hypoglycemic clamps, ICV catalase increased glucagon and epinephrine responses to hypoglycemia, consistent with perceived lower glucose levels. Our data suggest that H2O2 represents an important metabolic cue which, through tuning the electrical activity of key neuronal populations such as POMC neurons, may have a role in the brain's influence of glucose homeostasis and energy balance.",
author = "Markkula, {S Pauliina} and David Lyons and Chen-Yu Yueh and Christine Riches and Paul Hurst and Barbara Fielding and Heisler, {Lora K} and Evans, {Mark L}",
note = "Studies were funded by the Juvenile Diabetes Research Foundation (1–2006 –29) and Diabetes UK (RD05/003059) toMLE, the Wellcome Trust (WT098012) to LKH and Cambridge MRC Centre for Study of Obesity and Related Disorders (MRCCORD). In addition, PhD studentships/ fellowships were supported for SPM (Elmore Fund), PH (Sir Jules Thorn Trust) and C-YY Chang Gung University College of Medicine). We are grateful to Keith Burling and colleagues in the Cambridge MRCCORD and Department of Clinical Biochemistry, Cambridge University Hospitals NHS foundation trust (Addenbrookes Hospital), Cambridge for performing hormonal assays, to Dr Nicola Jackson (University of Surrey) for help with establishing the GC-MS method for plasma glucose stable isotope measure ments, to Mrs Jill Shaw for technical assistance with rodent studies and to Prof Malcolm Low (University of Michigan) for the generous gift of POMCDS-Red mice",
year = "2016",
month = "10",
day = "14",
doi = "10.1210/en.2015-2054",
language = "English",
volume = "157",
pages = "4669–4676",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "12",

}

TY - JOUR

T1 - Intracerebroventricular Catalase Reduces Hepatic Insulin Sensitivity and Increases Responses to Hypoglycemia in Rats

AU - Markkula, S Pauliina

AU - Lyons, David

AU - Yueh, Chen-Yu

AU - Riches, Christine

AU - Hurst, Paul

AU - Fielding, Barbara

AU - Heisler, Lora K

AU - Evans, Mark L

N1 - Studies were funded by the Juvenile Diabetes Research Foundation (1–2006 –29) and Diabetes UK (RD05/003059) toMLE, the Wellcome Trust (WT098012) to LKH and Cambridge MRC Centre for Study of Obesity and Related Disorders (MRCCORD). In addition, PhD studentships/ fellowships were supported for SPM (Elmore Fund), PH (Sir Jules Thorn Trust) and C-YY Chang Gung University College of Medicine). We are grateful to Keith Burling and colleagues in the Cambridge MRCCORD and Department of Clinical Biochemistry, Cambridge University Hospitals NHS foundation trust (Addenbrookes Hospital), Cambridge for performing hormonal assays, to Dr Nicola Jackson (University of Surrey) for help with establishing the GC-MS method for plasma glucose stable isotope measure ments, to Mrs Jill Shaw for technical assistance with rodent studies and to Prof Malcolm Low (University of Michigan) for the generous gift of POMCDS-Red mice

PY - 2016/10/14

Y1 - 2016/10/14

N2 - Specialized metabolic-sensors in the hypothalamus regulate blood glucose levels by influencing hepatic glucose output and hypoglycemic counter regulatory 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 H2O2 with the enzyme catalase would lead to systemic responses increasing blood glucose. During hyperinsulinemic euglycemic clamps in rats, ICV catalase infusion resulted in increased hepatic glucose output, which was associated with reduced neuronal activity in the arcuate nucleus of the hypothalamus (ARC). Electrophysiological recordings revealed a subset of ARC neurons expressing pro-opiomelanocortin (POMC) that were inhibited by catalase and excited by H2O2. During hypoglycemic clamps, ICV catalase increased glucagon and epinephrine responses to hypoglycemia, consistent with perceived lower glucose levels. Our data suggest that H2O2 represents an important metabolic cue which, through tuning the electrical activity of key neuronal populations such as POMC neurons, may have a role in the brain's influence of glucose homeostasis and energy balance.

AB - Specialized metabolic-sensors in the hypothalamus regulate blood glucose levels by influencing hepatic glucose output and hypoglycemic counter regulatory 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 H2O2 with the enzyme catalase would lead to systemic responses increasing blood glucose. During hyperinsulinemic euglycemic clamps in rats, ICV catalase infusion resulted in increased hepatic glucose output, which was associated with reduced neuronal activity in the arcuate nucleus of the hypothalamus (ARC). Electrophysiological recordings revealed a subset of ARC neurons expressing pro-opiomelanocortin (POMC) that were inhibited by catalase and excited by H2O2. During hypoglycemic clamps, ICV catalase increased glucagon and epinephrine responses to hypoglycemia, consistent with perceived lower glucose levels. Our data suggest that H2O2 represents an important metabolic cue which, through tuning the electrical activity of key neuronal populations such as POMC neurons, may have a role in the brain's influence of glucose homeostasis and energy balance.

U2 - 10.1210/en.2015-2054

DO - 10.1210/en.2015-2054

M3 - Article

VL - 157

SP - 4669

EP - 4676

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 12

ER -