Hypothalamic dopamine receptor D1 signaling mediates hedonic feeding-induced obesity

Obesity comorbidities such as diabetes and cardiovascular disease are pressing public health concerns. Overconsumption of calories leads to obesity; however, the neural mechanisms underlying excess food consumption and the resulting weight gain are poorly understood. Here, we find that similar to other addictive or compulsive behaviors, encoding of palatable food, via dopaminergic signaling in a homeostatic center of the brain, is responsible for short-circuiting the exquisite neural mechanisms in place to prevent overconsumption. We demonstrate that dopamine receptor D1 (Drd1) signaling is required for palatable diet induced hyperphagia outside of the regular meal time. Genetic ablation of Drd1 protects mice from diet-induced obesity and associated metabolic syndromes. Specifically, we identified a heterogeneous group of neurons expressing Drd1 in the arcuate hypothalamus (ARC) with a significant proportion co-expressing agouti-related peptide/neuropeptide Y (AgRP/NPY). We elucidated an orexigenic role of these Drd1-expressing neurons which regulate feeding behavior differently than the AgRP/NPY neurons. Furthermore, Drd1 expressed in the AgRP/NPY neurons is required for gating the severity of diet-induced obesity. Stimulation of the Drd1 and AgRP/NPY co-expressing arcuate neurons is sufficient to induce voracious feeding while genetic ablation of Drd1 in these neurons reduces hyperphagia and body weight gain induced by a palatable diet. In accordance with the orexigenic function of the Drd1-expressing neurons in the ARC, we revealed the dynamic DA release within the ARC, responding to changes of energy supplies. We identified a continuum of DA neurons in the hypothalamic areas projecting to the ARC, of which the genetically defined A13 DA group in the zona incerta (ZI) potentially promotes feeding by modulating ARC activity. These results provide a new mechanism that influences overconsumption of rewarding foods and positions Drd1 signaling in the ARCAgRP/NPY neurons as an integrator of the hedonic and homeostatic neuronal feeding circuits.