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

doi:10.1210/en.2015-2054

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

The Rowett Institute of Nutrition and Health

University of Cambridge
University of Aberdeen
Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM)
Wellcome Sanger Institute
University of Oxford

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

15 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 language	English
Pages (from-to)	4669–4676
Number of pages	8
Journal	Endocrinology
Volume	157
Issue number	12
DOIs	https://doi.org/10.1210/en.2015-2054
Publication status	Published - 14 Oct 2016

Bibliographical 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

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

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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{\textendash}2006 {\textendash}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",

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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

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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.

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DO - 10.1210/en.2015-2054

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SN - 0013-7227

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EP - 4676

JO - Endocrinology

JF - Endocrinology

IS - 12

ER -

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

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