1818-P: Brainstem GABAergic Circuits Regulating Energy Balance

Obesity is a serious disorder for which there is currently no effective treatment. The hypothalamus has long been studied as the critical node for regulating food intake and body weight; however, no effective targets have yet been identified within the hypothalamus for anti-obesity therapy. There is thus a critical, unmet need to identify other loci within the central nervous system that: a) potently regulate energy balance, through alterations in food intake and energy expenditure, and b) are potential therapeutic targets. We have recently found that the brainstem’s dorsal raphe nucleus (DRN) houses a small population of inhibitory, GABAergic neurons (hereafter DRN^Vgat neurons), which potently regulates energy balance, and concomitantly body weight. This is accomplished through the direct regulation of both food intake and energy expenditure, the latter component of which is achieved through both behavioral and physiologic mechanisms. However, the circuit mechanism(s) through which these neurons regulate energy homeostasis are poorly understood.

In recent work, we made the unexpected finding that DRN^Vgat neurons project broadly throughout the brain to differentially regulate both food intake and energy expenditure. In particular, we have found that these neurons exhibit both ascending projections (to the bed nucleus of the stria terminalis, dorsomedial hypothalamus, and medial preoptic area), as well as descending projections to the raphe pallidus. This latter, descending projection forms part of a polysynaptic circuit anatomically linking DRN^Vgat neurons to brown fat. Using projection-specific optogenetic manipulations, we have found that these projections can all potently suppress thermogenesis, and differentially regulate food intake. Critically, these effects are scalable, with higher stimulation intensities leading to increasing effects on both feeding and thermogenesis. Together, this work uncovers a novel circuit mechanism through which DRN^Vgat neurons regulate energy balance.