A molecularly defined NAcSh D1 subtype controls feeding and energy homeostasis

Orchestrating complex behavioral states, such as approach and consumption of food, is critical for survival. In addition to hypothalamus neuronal circuits, the nucleus accumbens (NAc) also plays an important role in controlling appetite and satiety in responses to changing external stimuli. However, the specific neuronal subtypes of NAc involved as well as how the humoral and neuronal signals coordinate to regulate feeding remain incompletely understood. Here, we deciphered the spatial diversity of neuron subtypes of the NAc shell (NAcSh) and defined a dopamine receptor D1(Drd1)- and Serpinb2-expressing subtype located in NAcSh encoding food consumption. Chemogenetics- and optogenetics-mediated regulation of Serpinb2 ⁺ neurons bidirectionally regulates food seeking and consumption specifically. Circuitry stimulation revealed the NAcSh ^Serpinb2 →LH ^LepR projection controls refeeding and can overcome leptin-mediated feeding suppression. Furthermore, NAcSh Serpinb2 ⁺ neuron ablation reduces food intake and upregulates energy expenditure resulting in body weight loss. Together, our study reveals a neural circuit consisted of molecularly distinct neuronal subtype that bidirectionally regulates energy homeostasis, which can serve as a potential therapeutic target for eating disorders.