Leptin modulates nutrient reward via inhibitory galanin action on orexin neurons

Highlights

• GAL-LepRb^KO shows ↓ galanin and ↓ GalR1 mRNA, ↑ body weight gain.

• GAL-LepRb^KO shows ↑ orexin/hypocretin neuronal activation.

• GAL-LepRb neurons innervate local orexin/hypocretin and noradrenergic locus coeruleus neurons.

• Leptin regulates natural reward and body weight via GAL-LepRb neurons.

Abstract

Objective

Leptin modulates food reward via central leptin receptor (LepRb) expressing neurons. Food reward requires stimulation of midbrain dopamine neurons and is modulated by central leptin action, but the exact central mechanisms remain unclear. Stimulatory and inhibitory leptin actions on dopamine neurons have been reported, e.g. by indirect actions on orexin neurons or via direct innervation of dopamine neurons in the ventral tegmental area.

Methods

We showed earlier that LepRb neurons in the lateral hypothalamus (LHA) co-express the inhibitory acting neuropeptide galanin (GAL-LepRb neurons). We studied the involvement of GAL-LepRb neurons to regulate nutrient reward in mice with selective LepRb deletion from galanin neurons (GAL-LepRb^KO mice).

Results

We found that the rewarding value and preference for sucrose over fat was increased in GAL-LepRb^KO mice compared to controls. LHA GAL-LepRb neurons innervate orexin neurons, but not the VTA. Further, expression of galanin and its receptor GalR1 are decreased in the LHA of GAL-LepRb^KO mice, resulting in increased activation of orexin neurons.

Conclusion

We suggest galanin as an important mediator of leptin action to modulate nutrient reward by inhibiting orexin neurons.