Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction

Abstract

Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRNVglut3) drive a robust suppression of food intake and enhance locomotion. Activating Vglut3 neurons in DRN suppresses food intake and increases locomotion, suggesting that modulating the activity of these neurons might alter body weight. Here, we show that DRNVglut3 neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRNVglut3 activation reduces weight in both leptin-deficient (ob/ob) and leptin-resistant diet-induced obese (DIO) male mice. Molecular profiling revealed that the orexin 1 receptor (Hcrtr1) is highly enriched in DRN Vglut3 neurons, with limited expression elsewhere in the brain. Finally, an orally bioavailable, highly selective Hcrtr1 antagonist (CVN45502) significantly reduces feeding and body weight in DIO. Hcrtr1 is also co-expressed with Vglut3 in the human DRN, suggesting that there might be a similar effect in human. These results identify a potential therapy for obesity by targeting DRNVglut3 neurons while also establishing a general strategy for developing drugs for central nervous system disorders.

Dorsal raphe serotonergic neurons suppress feeding through redundant forebrain circuits

“…Consistently, using fluorescent 5HT sensor we found that extracellular 5HT levels parallel the increased DRN SERT axonal activity. These findings are in line with earlier dialysis studies showing increased 5HT levels in LH in response to food and CCK and that DRN projections to LH is anorexigenic [ 20 , [27] , [28] , [29] ] and provides evidence that increased serotonergic activity extends to BNST as well. Together with axonal imaging, our results suggest that DRN is a key brain region supplying nutrient-related serotonergic input to these regions to suppress food intake.…”

Whole brain mapping of orexin receptor mRNA expression visualized by branchedin situhybridization chain reaction

“…The rough distribution of orexin receptors was reported in rat brains by radiolabeled probes approximately 20 years ago and is still the most comprehensive information available (23,24). Cell resolution information of OX1R and OX2R has been available only for brain regions that abundantly express orexin receptors, such as the amygdala, tuberomammillary nucleus, raphe nuclei, locus coeruleus, and laterodorsal tegmental nucleus (14,(25)(26)(27)(28). At this time, the Allen Brain Atlas fails to show positive signals for orexin receptors and reliable antibodies for OX1R and OX2R that work for immunohistochemistry are not available.…”

Leptin Activated Hypothalamic BNC2 Neurons Acutely Suppress Food Intake

“…These findings add an important new component to the neural circuit that regulates appetite and adiposity, while also shedding new light on the mechanisms by which leptin regulates this system. Finally, pharmacologic activation of these neurons could have therapeutic implications to reduce weight or to suppress the negative valence associated with hunger 66 .…”