Orexin neurons as conditional glucosensors: Paradoxical regulation of sugar sensing by intracellular fuels
Central orexin/hypocretin neurons promote wakefulness, feeding and reward-seeking, and control blood glucose levels by regulating sympathetic outflow to the periphery. Glucose itself directly suppresses the electrical activity and cytosolic calcium levels of orexin cells. Recentin vitrostudies sugge...
| Autores principales: | , , , , , |
|---|---|
| Formato: | Journal article |
| Lenguaje: | English |
| Publicado: |
2011
|
| _version_ | 1826292742212288512 |
|---|---|
| author | Venner, A Karnani, M Gonzalez, J Jensen, LT Fugger, L Burdakov, D |
| author_facet | Venner, A Karnani, M Gonzalez, J Jensen, LT Fugger, L Burdakov, D |
| author_sort | Venner, A |
| collection | OXFORD |
| description | Central orexin/hypocretin neurons promote wakefulness, feeding and reward-seeking, and control blood glucose levels by regulating sympathetic outflow to the periphery. Glucose itself directly suppresses the electrical activity and cytosolic calcium levels of orexin cells. Recentin vitrostudies suggested that glucose inhibition of orexin cells may be mechanistically unusual, because it persists under conditions where glucose metabolism is unlikely. To investigate this further, and to clarify whether background metabolic state regulates orexin cell glucosensing, here we analysed glucose responses of orexin cells in mouse brain slices, in the presence and absence of metabolic inhibitors and physiological energy substrates. Consistent with their documented insensitivity to glucokinase inhibitors, the glucose responses of orexin cells persisted in the presence of the mitochondrial poison oligomycin or the glial toxin fluoroacetate. Unexpectedly, in the presence of oligomycin, the magnitude of the glucose response was significantly enhanced. In turn, 2-deoxyglucose, a non-metabolizable glucose analogue, elicited larger responses than glucose. Conversely, intracellular pyruvate dose-dependently suppressed the glucose responses, an effect that was blocked by oligomycin. The glucose responses were also suppressed by intracellular lactate and ATP. Our new data suggest that other energy substrates not only fail to mimic the orexin glucose response, but paradoxically suppress it in a metabolism-dependent manner. We propose that this unexpected intrinsic property of orexin cells allows them to act as 'conditional glucosensors' that preferentially respond to glucose during reduced background energy levels. © 2011 The Authors. Journal compilation © 2011 The Physiological Society. |
| first_indexed | 2024-03-07T03:19:23Z |
| format | Journal article |
| id | oxford-uuid:b6eb2299-4868-4bc8-8a4a-cbf68922e81a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:19:23Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:b6eb2299-4868-4bc8-8a4a-cbf68922e81a2022-03-27T04:44:34ZOrexin neurons as conditional glucosensors: Paradoxical regulation of sugar sensing by intracellular fuelsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:b6eb2299-4868-4bc8-8a4a-cbf68922e81aEnglishSymplectic Elements at Oxford2011Venner, AKarnani, MGonzalez, JJensen, LTFugger, LBurdakov, DCentral orexin/hypocretin neurons promote wakefulness, feeding and reward-seeking, and control blood glucose levels by regulating sympathetic outflow to the periphery. Glucose itself directly suppresses the electrical activity and cytosolic calcium levels of orexin cells. Recentin vitrostudies suggested that glucose inhibition of orexin cells may be mechanistically unusual, because it persists under conditions where glucose metabolism is unlikely. To investigate this further, and to clarify whether background metabolic state regulates orexin cell glucosensing, here we analysed glucose responses of orexin cells in mouse brain slices, in the presence and absence of metabolic inhibitors and physiological energy substrates. Consistent with their documented insensitivity to glucokinase inhibitors, the glucose responses of orexin cells persisted in the presence of the mitochondrial poison oligomycin or the glial toxin fluoroacetate. Unexpectedly, in the presence of oligomycin, the magnitude of the glucose response was significantly enhanced. In turn, 2-deoxyglucose, a non-metabolizable glucose analogue, elicited larger responses than glucose. Conversely, intracellular pyruvate dose-dependently suppressed the glucose responses, an effect that was blocked by oligomycin. The glucose responses were also suppressed by intracellular lactate and ATP. Our new data suggest that other energy substrates not only fail to mimic the orexin glucose response, but paradoxically suppress it in a metabolism-dependent manner. We propose that this unexpected intrinsic property of orexin cells allows them to act as 'conditional glucosensors' that preferentially respond to glucose during reduced background energy levels. © 2011 The Authors. Journal compilation © 2011 The Physiological Society. |
| spellingShingle | Venner, A Karnani, M Gonzalez, J Jensen, LT Fugger, L Burdakov, D Orexin neurons as conditional glucosensors: Paradoxical regulation of sugar sensing by intracellular fuels |
| title | Orexin neurons as conditional glucosensors: Paradoxical regulation of sugar sensing by intracellular fuels |
| title_full | Orexin neurons as conditional glucosensors: Paradoxical regulation of sugar sensing by intracellular fuels |
| title_fullStr | Orexin neurons as conditional glucosensors: Paradoxical regulation of sugar sensing by intracellular fuels |
| title_full_unstemmed | Orexin neurons as conditional glucosensors: Paradoxical regulation of sugar sensing by intracellular fuels |
| title_short | Orexin neurons as conditional glucosensors: Paradoxical regulation of sugar sensing by intracellular fuels |
| title_sort | orexin neurons as conditional glucosensors paradoxical regulation of sugar sensing by intracellular fuels |
| work_keys_str_mv | AT vennera orexinneuronsasconditionalglucosensorsparadoxicalregulationofsugarsensingbyintracellularfuels AT karnanim orexinneuronsasconditionalglucosensorsparadoxicalregulationofsugarsensingbyintracellularfuels AT gonzalezj orexinneuronsasconditionalglucosensorsparadoxicalregulationofsugarsensingbyintracellularfuels AT jensenlt orexinneuronsasconditionalglucosensorsparadoxicalregulationofsugarsensingbyintracellularfuels AT fuggerl orexinneuronsasconditionalglucosensorsparadoxicalregulationofsugarsensingbyintracellularfuels AT burdakovd orexinneuronsasconditionalglucosensorsparadoxicalregulationofsugarsensingbyintracellularfuels |