Leptin activation of dorsal raphe neurons inhibits feeding behavior

AbstractLeptin is a homeostatic regulatory element that signals the presence of adipocyte energy stores, reduces food intake, and increases energy expenditure. Similarly, serotonin (5-HT), a signaling molecule found in both the central and peripheral nervous systems, also controls food intake. Using neuronal tract-tracing, pharmacological and optogenetics approaches, and in vivo microdialysis, combined with behavioral endpoints, we tested the hypothesis that leptin controls food intake not only by activating hypothalamic leptin receptors (LepRs), but also through activation of LepRs expressed by serotonergic raphe neurons that send projections to the arcuate (ARC). We show that microinjection of leptin directly into the dorsal raphe nucleus (DRN) reduces food intake in rats. This effect is mediated by LepR expressing neurons in the DRN as selective optogenetic activation of these neurons at either their DRN cell bodies or their ARC terminals reduces food intake. Anatomically, we identified a unique population of serotonergic raphe neurons expressing LepRs that send projections to the ARC. Finally, by utilizing in vivo microdialysis, we show that leptin administration to the DRN increases 5-HT efflux into the ARC, and specific antagonism of the 5-HT2C receptors in the ARC diminishes the leptin anorectic effect. Overall, this study identifies a novel circuit for leptin-mediated control of food intake through a DRN-ARC pathway, identifying a new level of interaction between leptin and serotonin to control food intake. Characterization of this new pathway creates opportunities for understanding how the brain controls eating behavior, as well as opens alternative routes for the treatment of eating disorders.Article Highlights· Half of serotonergic neurons in the dorsal raphe nucleus express leptin receptor mRNA.· Activation of these raphe neurons expressing leptin receptors has an anorectic effect.· Optogenetic activation of the arcuate terminals of these raphe neurons decreases food intake.· Leptin administration directly to the dorsal raphe nucleus increases serotonin efflux in the arcuate. Blockade of the serotonergic receptors in the arcuate attenuates the anorectic effect of leptin injected into the raphe.