Lateral hypothalamus hypocretin/orexin glucose-inhibited neurons promote food seeking after calorie restriction
Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved..
OBJECTIVE: The present study tests the hypothesis that changes in the glucose sensitivity of lateral hypothalamus (LH) hypocretin/orexin glucose-inhibited (GI) neurons following weight loss leads to glutamate plasticity on ventral tegmental area (VTA) dopamine neurons and drives food seeking behavior.
METHODS: C57BL/6J mice were calorie restricted to a 15% body weight loss and maintained at that body weight for 1 week. The glucose sensitivity of LH hypocretin/orexin GI and VTA dopamine neurons was measured using whole cell patch clamp recordings in brain slices. Food seeking behavior was assessed using conditioned place preference (CPP).
RESULTS: 1-week maintenance of calorie restricted 15% body weight loss reduced glucose inhibition of hypocretin/orexin GI neurons resulting in increased neuronal activation with reduced glycemia. The effect of decreased glucose on hypocretin/orexin GI neuronal activation was blocked by pertussis toxin (inhibitor of G-protein coupled receptor subunit Gαi/o) and Rp-cAMP (inhibitor of protein kinase A, PKA). This suggests that glucose sensitivity is mediated by the Gαi/o-adenylyl cyclase-cAMP-PKA signaling pathway. The excitatory effect of the hunger hormone, ghrelin, on hcrt/ox neurons was also blocked by Rp-cAMP suggesting that hormonal signals of metabolic status may converge on the glucose sensing pathway. Food restriction and weight loss increased glutamate synaptic strength (indexed by increased AMPA/NMDA receptor current ratio) on VTA dopamine neurons and the motivation to seek food (indexed by CPP). Chemogenetic inhibition of hypocretin/orexin neurons during caloric restriction and weight loss prevented these changes in glutamate plasticity and food seeking behavior.
CONCLUSIONS: We hypothesize that this change in the glucose sensitivity of hypocretin/orexin GI neurons may drive, in part, food seeking behavior following caloric restriction.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:76 |
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| Enthalten in: |
Molecular metabolism - 76(2023) vom: 01. Okt., Seite 101788 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Teegala, Suraj B [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 11.09.2023 Date Revised 28.09.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.molmet.2023.101788 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Teegala, Suraj B |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Lateral hypothalamus hypocretin/orexin glucose-inhibited neurons promote food seeking after calorie restriction |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 11.09.2023 | ||
| 500 | |a Date Revised 28.09.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved. | ||
| 520 | |a OBJECTIVE: The present study tests the hypothesis that changes in the glucose sensitivity of lateral hypothalamus (LH) hypocretin/orexin glucose-inhibited (GI) neurons following weight loss leads to glutamate plasticity on ventral tegmental area (VTA) dopamine neurons and drives food seeking behavior | ||
| 520 | |a METHODS: C57BL/6J mice were calorie restricted to a 15% body weight loss and maintained at that body weight for 1 week. The glucose sensitivity of LH hypocretin/orexin GI and VTA dopamine neurons was measured using whole cell patch clamp recordings in brain slices. Food seeking behavior was assessed using conditioned place preference (CPP) | ||
| 520 | |a RESULTS: 1-week maintenance of calorie restricted 15% body weight loss reduced glucose inhibition of hypocretin/orexin GI neurons resulting in increased neuronal activation with reduced glycemia. The effect of decreased glucose on hypocretin/orexin GI neuronal activation was blocked by pertussis toxin (inhibitor of G-protein coupled receptor subunit Gαi/o) and Rp-cAMP (inhibitor of protein kinase A, PKA). This suggests that glucose sensitivity is mediated by the Gαi/o-adenylyl cyclase-cAMP-PKA signaling pathway. The excitatory effect of the hunger hormone, ghrelin, on hcrt/ox neurons was also blocked by Rp-cAMP suggesting that hormonal signals of metabolic status may converge on the glucose sensing pathway. Food restriction and weight loss increased glutamate synaptic strength (indexed by increased AMPA/NMDA receptor current ratio) on VTA dopamine neurons and the motivation to seek food (indexed by CPP). Chemogenetic inhibition of hypocretin/orexin neurons during caloric restriction and weight loss prevented these changes in glutamate plasticity and food seeking behavior | ||
| 520 | |a CONCLUSIONS: We hypothesize that this change in the glucose sensitivity of hypocretin/orexin GI neurons may drive, in part, food seeking behavior following caloric restriction | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Conditioned-place preference | |
| 650 | 4 | |a Dopamine | |
| 650 | 4 | |a Electrophysiology | |
| 650 | 4 | |a Ghrelin | |
| 650 | 4 | |a Glutamate plasticity | |
| 650 | 4 | |a Protein kinase A | |
| 650 | 7 | |a Orexins |2 NLM | |
| 650 | 7 | |a Neuropeptides |2 NLM | |
| 650 | 7 | |a Glucose |2 NLM | |
| 650 | 7 | |a IY9XDZ35W2 |2 NLM | |
| 650 | 7 | |a Glutamates |2 NLM | |
| 700 | 1 | |a Sarkar, Pallabi |e verfasserin |4 aut | |
| 700 | 1 | |a Siegel, Dashiel M |e verfasserin |4 aut | |
| 700 | 1 | |a Sheng, Zhenyu |e verfasserin |4 aut | |
| 700 | 1 | |a Hao, Lihong |e verfasserin |4 aut | |
| 700 | 1 | |a Bello, Nicholas T |e verfasserin |4 aut | |
| 700 | 1 | |a De Lecea, Luis |e verfasserin |4 aut | |
| 700 | 1 | |a Beck, Kevin D |e verfasserin |4 aut | |
| 700 | 1 | |a Routh, Vanessa H |e verfasserin |4 aut | |
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