Lateral hypothalamus hypocretin/orexin glucose-inhibited neurons promote food seeking after calorie restriction

• Published in: Molecular metabolism (Germany) Vol. 76; p. 101788
• Main Authors: Teegala, Suraj B., Sarkar, Pallabi, Siegel, Dashiel M., Sheng, Zhenyu, Hao, Lihong, Bello, Nicholas T., De Lecea, Luis, Beck, Kevin D., Routh, Vanessa H.
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.10.2023; Elsevier
• Subjects: Conditioned-place preference; Dopamine; Electrophysiology; Ghrelin; Glutamate plasticity; Original; Protein kinase A; Protein kinase A; Electrophysiology; Conditioned-place preference; Glutamate plasticity; Dopamine; Ghrelin; ghrelin; electrophysiology; protein kinase A; dopamine; glutamate plasticity; conditioned-place preference
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2023.101788

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. 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). 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. We hypothesize that this change in the glucose sensitivity of hypocretin/orexin GI neurons may drive, in part, food seeking behavior following caloric restriction. •Calorie restriction and weight loss alter glucose sensitivity of hypocretin/orexin GI neurons.•Calorie restriction increases glutamate signaling on midbrain dopamine neurons.•Hypocretin/orexin mediates the effects of calorie restriction on dopamine neurons and feeding.•Glucose and ghrelin regulate hypocretin/orexin neurons via protein kinase A.