Thalamic opioids from POMC satiety neurons gate sugar appetite

Sweet, high-sugar containing foods are extremely palatable and often consumed in the absence of caloric needs, thereby driving positive energy balance and accelerating obesity development. Pharmacological studies suggest that endogenous opioid signaling in the brain mediates this specific appetite for sugar in satiety states; however, the cellular and circuit mechanisms remain unknown. We find that pro-opiomelanocortin (POMC) neurons, which are well known for their satiety promoting effects via the melanocortin-4 receptor system, selectively inhibit postsynaptic neurons in the paraventricular thalamus (PVT) through the activation of mu-opioid receptors. In vivo calcium imaging demonstrates that this POMC → PVT opioid circuit is strongly activated during sugar consumption, which is most notable when energy stores are replete or acutely replenished. Correspondingly, chemogenetic manipulation experiments demonstrate that its inhibition diminishes high-sugar diet consumption in fed and acutely satiated mice. Importantly, histological and imaging studies demonstrate that the POMC → PVT opioid circuit is anatomically and functionally conserved in humans. Together, these findings uncover that POMC neurons not only promote satiety in energy repleted states, but at the same time increase the specific appetite for sugar, thereby providing a potential new target for the prevention and treatment of obesity.