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Metabolism-independent sugar sensing in central orexin neurons.

González JA, Jensen LT, Fugger L, Burdakov D - Diabetes (2008)

Bottom Line: Orexin/hypocretin neurons of the lateral hypothalamus are widely projecting glucose-inhibited cells essential for normal cognitive arousal and feeding behavior.RESULTS- We show that 1) 2-deoxyglucose, a nonmetabolizable glucose analog, mimics the effects of glucose; 2) increasing intracellular energy fuel production with lactate does not reproduce glucose responses; 3) orexin cell glucose sensing is unaffected by glucokinase inhibitors alloxan, d-glucosamine, and N-acetyl-d-glucosamine; and 4) orexin glucosensors detect mannose, d-glucose, and 2-deoxyglucose but not galactose, l-glucose, alpha-methyl-d-glucoside, or fructose.Our new data suggest that behaviorally critical neurocircuits of the lateral hypothalamus contain glucose detectors that exhibit novel sugar selectivity and can operate independently of glucose metabolism.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Cambridge, Cambridge, UK.

ABSTRACT

Objective: Glucose sensing by specialized neurons of the hypothalamus is vital for normal energy balance. In many glucose-activated neurons, glucose metabolism is considered a critical step in glucose sensing, but whether glucose-inhibited neurons follow the same strategy is unclear. Orexin/hypocretin neurons of the lateral hypothalamus are widely projecting glucose-inhibited cells essential for normal cognitive arousal and feeding behavior. Here, we used different sugars, energy metabolites, and pharmacological tools to explore the glucose-sensing strategy of orexin cells.

Research design and methods: We carried out patch-clamp recordings of the electrical activity of individual orexin neurons unambiguously identified by transgenic expression of green fluorescent protein in mouse brain slices. RESULTS- We show that 1) 2-deoxyglucose, a nonmetabolizable glucose analog, mimics the effects of glucose; 2) increasing intracellular energy fuel production with lactate does not reproduce glucose responses; 3) orexin cell glucose sensing is unaffected by glucokinase inhibitors alloxan, d-glucosamine, and N-acetyl-d-glucosamine; and 4) orexin glucosensors detect mannose, d-glucose, and 2-deoxyglucose but not galactose, l-glucose, alpha-methyl-d-glucoside, or fructose.

Conclusions: Our new data suggest that behaviorally critical neurocircuits of the lateral hypothalamus contain glucose detectors that exhibit novel sugar selectivity and can operate independently of glucose metabolism.

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Effects of 2-deoxyglucose on cortical neurons. A: Effect of 2-deoxyglucose on the membrane potential. Breaks in the trace correspond to where the recording was interrupted to expose the cell to voltage-clamp ramps (see research design and methods). Arrows show where the voltage-clamp ramps shown in B were taken. B: Effect of 2-deoxyglucose on membrane current-voltage relationship of the cell shown in A. No activation of K+ current is observed, but 2-deoxyglucose inhibits a current with a reversal potential of about −50 mV.
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f3: Effects of 2-deoxyglucose on cortical neurons. A: Effect of 2-deoxyglucose on the membrane potential. Breaks in the trace correspond to where the recording was interrupted to expose the cell to voltage-clamp ramps (see research design and methods). Arrows show where the voltage-clamp ramps shown in B were taken. B: Effect of 2-deoxyglucose on membrane current-voltage relationship of the cell shown in A. No activation of K+ current is observed, but 2-deoxyglucose inhibits a current with a reversal potential of about −50 mV.

Mentions: Current-voltage relationships (Figs. 2A and B, 3B, 4B, 5B and C, and 7B and C) were obtained by performing voltage-clamp ramps from 0 to −140 mV at a rate of 0.1 mV/ms ramp, which is sufficiently slow to allow leak-like K+ currents to reach steady state at each potential (28). In Figs. 2B and 7C, the net current-voltage relationship was fitted with the Goldman-Hodgkin-Katz (GHK) current equation (29) in the following form: \documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}I=P_{{\mathrm{K}}}z^{2}\frac{VF^{2}}{RT}\frac{[{\mathrm{K}}^{+}]_{i}-[{\mathrm{K}}^{+}]_{0}{\mathrm{exp}}(-zFV/RT)}{1-{\mathrm{exp}}(-zFV/RT)}\end{equation*}\end{document}


Metabolism-independent sugar sensing in central orexin neurons.

González JA, Jensen LT, Fugger L, Burdakov D - Diabetes (2008)

Effects of 2-deoxyglucose on cortical neurons. A: Effect of 2-deoxyglucose on the membrane potential. Breaks in the trace correspond to where the recording was interrupted to expose the cell to voltage-clamp ramps (see research design and methods). Arrows show where the voltage-clamp ramps shown in B were taken. B: Effect of 2-deoxyglucose on membrane current-voltage relationship of the cell shown in A. No activation of K+ current is observed, but 2-deoxyglucose inhibits a current with a reversal potential of about −50 mV.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2551664&req=5

f3: Effects of 2-deoxyglucose on cortical neurons. A: Effect of 2-deoxyglucose on the membrane potential. Breaks in the trace correspond to where the recording was interrupted to expose the cell to voltage-clamp ramps (see research design and methods). Arrows show where the voltage-clamp ramps shown in B were taken. B: Effect of 2-deoxyglucose on membrane current-voltage relationship of the cell shown in A. No activation of K+ current is observed, but 2-deoxyglucose inhibits a current with a reversal potential of about −50 mV.
Mentions: Current-voltage relationships (Figs. 2A and B, 3B, 4B, 5B and C, and 7B and C) were obtained by performing voltage-clamp ramps from 0 to −140 mV at a rate of 0.1 mV/ms ramp, which is sufficiently slow to allow leak-like K+ currents to reach steady state at each potential (28). In Figs. 2B and 7C, the net current-voltage relationship was fitted with the Goldman-Hodgkin-Katz (GHK) current equation (29) in the following form: \documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}I=P_{{\mathrm{K}}}z^{2}\frac{VF^{2}}{RT}\frac{[{\mathrm{K}}^{+}]_{i}-[{\mathrm{K}}^{+}]_{0}{\mathrm{exp}}(-zFV/RT)}{1-{\mathrm{exp}}(-zFV/RT)}\end{equation*}\end{document}

Bottom Line: Orexin/hypocretin neurons of the lateral hypothalamus are widely projecting glucose-inhibited cells essential for normal cognitive arousal and feeding behavior.RESULTS- We show that 1) 2-deoxyglucose, a nonmetabolizable glucose analog, mimics the effects of glucose; 2) increasing intracellular energy fuel production with lactate does not reproduce glucose responses; 3) orexin cell glucose sensing is unaffected by glucokinase inhibitors alloxan, d-glucosamine, and N-acetyl-d-glucosamine; and 4) orexin glucosensors detect mannose, d-glucose, and 2-deoxyglucose but not galactose, l-glucose, alpha-methyl-d-glucoside, or fructose.Our new data suggest that behaviorally critical neurocircuits of the lateral hypothalamus contain glucose detectors that exhibit novel sugar selectivity and can operate independently of glucose metabolism.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Cambridge, Cambridge, UK.

ABSTRACT

Objective: Glucose sensing by specialized neurons of the hypothalamus is vital for normal energy balance. In many glucose-activated neurons, glucose metabolism is considered a critical step in glucose sensing, but whether glucose-inhibited neurons follow the same strategy is unclear. Orexin/hypocretin neurons of the lateral hypothalamus are widely projecting glucose-inhibited cells essential for normal cognitive arousal and feeding behavior. Here, we used different sugars, energy metabolites, and pharmacological tools to explore the glucose-sensing strategy of orexin cells.

Research design and methods: We carried out patch-clamp recordings of the electrical activity of individual orexin neurons unambiguously identified by transgenic expression of green fluorescent protein in mouse brain slices. RESULTS- We show that 1) 2-deoxyglucose, a nonmetabolizable glucose analog, mimics the effects of glucose; 2) increasing intracellular energy fuel production with lactate does not reproduce glucose responses; 3) orexin cell glucose sensing is unaffected by glucokinase inhibitors alloxan, d-glucosamine, and N-acetyl-d-glucosamine; and 4) orexin glucosensors detect mannose, d-glucose, and 2-deoxyglucose but not galactose, l-glucose, alpha-methyl-d-glucoside, or fructose.

Conclusions: Our new data suggest that behaviorally critical neurocircuits of the lateral hypothalamus contain glucose detectors that exhibit novel sugar selectivity and can operate independently of glucose metabolism.

Show MeSH