Reversal of obesogenic feeding and hypometabolism by a bifurcating GABAergic neural circuit

Diet-induced obesity is characterized by unsatiated consumption of energy-dense diets and impaired metabolism, whereby anti-obesity effect of the high-level of circulating leptin is unknowingly blunted. Emerging evidence suggests that the leptin receptor (LepR) signaling system, residing within the agouti-related protein (AgRP) neurons of the hypothalamus, critically contributes to obesogenic feeding, nutrient partitioning, and energy metabolism. However, the neural circuit mechanism underlying the leptin-dependent control of obesogenic feeding and energy balance remains largely elusive. Here, we show that two distinct subgroups of LepR-expressing AgRP neurons send non-collateral, GABAergic projections to the dorsomedial hypothalamic nucleus (DMH) and to the medial part of the medial preoptic nucleus (MPO) for the differential control of metabolic homeostasis and obesogenic feeding, respectively. We found that the AgRP^LepR-DMH neural circuit plays a significant role in leptin-dependent control of metabolic homeostasis through the α3-containing GABA_A receptor signaling on the melanocortin 4 receptor neurons within the DMH (MC4R^DMH). In contrast, the AgRP^LepR-MPO neural circuit elicits dominant effects on the appetitive response to high-fat diet through the α2-containing GABA_A receptors on the MC4R^MPO neurons. Consistent with these behavioral results, the post-synaptic GABA_A neurons located within the DMH and MPO displayed differentiated firing responses under various feeding and nutrient conditions. Our results demonstrate that these novel GABAergic neural circuits exert differentiated control of metabolic hemostasis and obesogenic feeding via distinct post-synaptic targets of leptin-responsive AgRP neurons. The findings of two genetically and anatomically distinct GABA_A receptor signaling pathways within the DMH and MPO would undoubtedly accelerate the development of targeted, individualized, anti-obesity therapy.