Event Abstract

Effects of sugar on sleep, appetite, and reward circuits of the brain

  • 1 University of Cambridge, Department of Pharmacology, United Kingdom

Both simple and complex aspects of behaviour are strongly linked to body energy levels. In recent years, it became clear that this link extends beyond the obvious effects of changes in fuel availability on fuel-requiring processes. In the brain, there are numerous nutrient sensors that can detect minute fluctuations and trends in body energy balance, and try to trigger useful adaptive behaviours, before fuel levels reach pathological boundaries. To begin to look at the cellular and molecular bases of these processes in mammals, we focussed on the orexin/hypocretin-producing neurons of the mouse hypothalamus. The firing of this widely-projecting neural cluster promotes awakening, and loss of orexin/hypocretin neurons results in narcolepsy/cataplexy. In addition, orexin/hypocretin neurons stimulate feeding and play vital roles in reward-seeking and drug addiction. Orexin/hypocretin neurons also act as selective sugar sensors, and their firing is suppressed by glucose elevations in the physiological range, due to glucose-induced opening of background potassium channels (D. Burdakov et al., 2005,D. Burdakov et al., 2006). Thus, this neural network may provide a direct link between changes in sugar levels, and orchestration of sleep, appetite, and reward. This lecture reviews some of our recent findings on how orexin/hypocretin neurons translate sugar levels into changes in their activity.

In many glucose-activated neurons, glucose metabolism is considered a critical step in glucose sensing. We found that in orexin/hypocretic neurons, 2-deoxyglucose, a non-metabolizable glucose analogue, has similar inhibitory effects to glucose. In turn, stimulating ATP production with lactate does not reproduce glucose responses. Orexin/hypocretin cellglucose-sensing is also unaffected by glucokinase inhibitors such as alloxan, d-glucosamine, and N-acetyl-d-glucosamine.In terms of agonist pharmacology, orexinglucosensors are activated by mannose, d-glucose, and 2-deoxyglucose, but not by galactose, l-glucose, a-methyl-d-glucoside, or fructose. Thus orexin/hypocretin neurons exhibit novel sugar selectivity and can operate independently of glucose metabolism (discussed further in J. A. Gonzalez et al., 2008; J. A. Gonzalez et al., 2009).

Another key question is how orexin/hypocretin circuits encode both small changes and large background values of sugar levels, while also maintaining an activity tone necessary for stable wakefulness. We found orexin neurons are dichotomous in their sugar-sensing and basic electrical properties. A distinct group of orexin neurons exhibits only temporary inhibitory responses to rises in sugar levels, via a time-dependent recovery from inhibition via adaptive closure of K+ channels. Combining transient and sustained responses to sugarin different orexin neurons presumably allows theorexinsystem to maintain sensitivity to small fluctuations in glucose levels while simultaneously encoding a large range of baseline glucose concentrations (discussed further in R. H. Williams et al., 2008).

This lecture will discuss the above findings in the context of wider regulation of sleep, appetite, and reward-seeking in mammals, and relate them to integration of other types of signals such as neuropeptides and gasses (R. H. Williams et al., 2007; A. Gonzalez et al., 2009) by orexin/hypocretin circuits.


1. Burdakov D, Gerasimenko O, Verkhratsky A (2005) Physiological changes in glucose differentially modulate the excitability of hypothalamic melanin-concentrating hormone and orexin neurons in situ. J Neurosci 25:2429-2433.

2. Burdakov D, Jensen LT, Alexopoulos H, Williams RH, Fearon IM, O'Kelly I, Gerasimenko O, Fugger L, Verkhratsky A (2006) Tandem-pore K+ channels mediate inhibition of orexin neurons by glucose. Neuron 50:711-722.

3. Gonzalez A, Horjales-Araujo E, Fugger L, Broberger C, Burdakov D (2009) Stimulation of orexin/hypocretin neurones by thyrotropin-releasing hormone. J Physiol.

4. Gonzalez JA, Reimann F, Burdakov D (2009) Dissociation between sensing and metabolism of glucose in sugar sensing neurones. J Physiol 587:41-48.

5. Gonzalez JA, Jensen LT, Fugger L, Burdakov D (2008) Metabolism-independent sugar sensing in central orexin neurons. Diabetes 57:2569-2576.

6. Williams RH, Jensen LT, Verkhratsky A, Fugger L, Burdakov D (2007) Control of hypothalamic orexin neurons by acid and CO2. Proc NatlAcadSci U S A 104:10685-10690.

7. Williams RH, Alexopoulos H, Jensen LT, Fugger L, Burdakov D (2008) Adaptive sugar sensors in hypothalamic feeding circuits. Proc NatlAcadSci U S A 105:11975-11980.

Conference: 2nd Selfish Brain Conference
New research on the neurobiology of ingestive behaviour, 23554 Luebeck, Germany, 27 May - 28 May, 2010.

Presentation Type: Oral Presentation

Topic: Talks

Citation: Burdakov D (2010). Effects of sugar on sleep, appetite, and reward circuits of the brain. Front. Neurosci. Conference Abstract: 2nd Selfish Brain Conference
New research on the neurobiology of ingestive behaviour.
doi: 10.3389/conf.fnins.2010.08.00014

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Received: 12 Apr 2010; Published Online: 12 Apr 2010.

* Correspondence: Denis Burdakov, University of Cambridge, Department of Pharmacology, Cambridge, United Kingdom, denis.burdakov@kcl.ac.uk