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 (H$_2$O$_2$), a relatively stable form of ROS, acts as a sensor of neuronal glucose consumption and availability and that lowering brain H$_2$O$_2$ 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 H$_2$O$_2$. During hypoglycemic clamps, ICV catalase increased glucagon and epinephrine responses to hypoglycemia, consistent with perceived lower glucose levels. Our data suggest that H$_2$O$_2$ 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.This work was supported by the Juvenile Diabetes Research Foundation Grant 1-2006-29 and the Diabetes UK Grant RD05/ 003059 (to M.L.E.), the Wellcome Trust Grant WT098012 (to L.K.H.), and Cambridge Medical Research Council Centre for Study of Obesity and Related Disorders. In addition, PhD studentships/fellowships were supported for S.P.M. (Elmore Fund), P.H. (Sir Jules Thorn Trust), and C.-Y.Y. (Chang Gung University College of Medicine Grant numbers CMRPG6B0291 and CMRPG6B0292)