Glucokinase activity in the arcuate nucleus regulates glucose intake
Syed Hussain, … , Steve Bloom, James Gardiner
Syed Hussain, … , Steve Bloom, James Gardiner
Published December 8, 2014
Citation Information: J Clin Invest. 2015;125(1):337-349. https://doi.org/10.1172/JCI77172.
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Research Article Endocrinology

Glucokinase activity in the arcuate nucleus regulates glucose intake

Abstract

The brain relies on a constant supply of glucose, its primary fuel, for optimal function. A taste-independent mechanism within the CNS that promotes glucose delivery to the brain has been postulated to maintain glucose homeostasis; however, evidence for such a mechanism is lacking. Here, we determined that glucokinase activity within the hypothalamic arcuate nucleus is involved in regulation of dietary glucose intake. In fasted rats, glucokinase activity was specifically increased in the arcuate nucleus but not other regions of the hypothalamus. Moreover, pharmacologic and genetic activation of glucokinase in the arcuate nucleus of rodent models increased glucose ingestion, while decreased arcuate nucleus glucokinase activity reduced glucose intake. Pharmacologic targeting of potential downstream glucokinase effectors revealed that ATP-sensitive potassium channel and P/Q calcium channel activity are required for glucokinase-mediated glucose intake. Additionally, altered glucokinase activity affected release of the orexigenic neurotransmitter neuropeptide Y in response to glucose. Together, our results suggest that glucokinase activity in the arcuate nucleus specifically regulates glucose intake and that appetite for glucose is an important driver of overall food intake. Arcuate nucleus glucokinase activation may represent a CNS mechanism that underlies the oft-described phenomena of the “sweet tooth” and carbohydrate craving.

Authors

Syed Hussain, Errol Richardson, Yue Ma, Christopher Holton, Ivan De Backer, Niki Buckley, Waljit Dhillo, Gavin Bewick, Shuai Zhang, David Carling, Steve Bloom, James Gardiner

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Figure 2

Effect of increased arcuate nucleus glucokinase activity on glucose intake.

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Effect of increased arcuate nucleus glucokinase activity on glucose inta...
(A) 2% w/v glucose solution intake 1 hour after intra-arcuate injection of CpdA or control in rats (n = 7). Twenty-four hour intake of (B) 2% w/v and (C) 10% w/v glucose and fructose solutions in iARC-GFP (white bars) and iARC-GK rats (black bars) (n = 8). (D) 2% w/v glucose solution intake and (E) food intake 1 hour after intra-arcuate injection of CpdA or vehicle in rats with ad libitum access to 2% w/v glucose solution and normal chow (n = 7). (F) 2% w/v glucose solution intake, (G) food intake, and (H) energy intake in iARC-GFP (black circles) and iARC-GK (white squares) rats during a 24-hour feeding study, with ad libitum access to 2% w/v glucose solution and normal chow intake (n = 7). (I) Food intake in iARC-GFP (black circles) and iARC-GK (white squares) rats (n = 7) during a 24-hour feeding study, with ad libitum access to normal chow diet only. (J) 10% w/v glucose, (K) food intake with normal chow, (L) total energy intake, and (M) weight changes in iARC-GFP (black circles) and iARC-GK (white squares) rats with ad libitum access to normal chow diet and 10% w/v glucose given 4 weeks after rAAV microinjection (n = 8). Data are presented as mean ± SEM *P < 0.05, **P < 0.01, ***P < 0.001.