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

Mol Metab. 2023 Oct:76:101788. doi: 10.1016/j.molmet.2023.101788. Epub 2023 Aug 2.

Abstract

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.

Keywords: Conditioned-place preference; Dopamine; Electrophysiology; Ghrelin; Glutamate plasticity; Protein kinase A.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Caloric Restriction
  • Dopaminergic Neurons / metabolism
  • Glucose / metabolism
  • Glutamates / metabolism
  • Glutamates / pharmacology
  • Hypothalamic Area, Lateral* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neuropeptides* / metabolism
  • Orexins / metabolism

Substances

  • Orexins
  • Neuropeptides
  • Glucose
  • Glutamates