A brain-derived insulin signal encodes protein satiety for nutrient-specific feeding inhibition

The suppressive effect of insulin on food intake has been documented for decades. However, whether insulin signals can encode a certain type of nutrients to regulate nutrient-specific feeding behavior remains elusive. Here, we show that in female Drosophila, a pair of dopaminergic neurons, tritocerebrum 1-dopaminergic neurons (T1-DANs), are directly activated by a protein-intake-induced insulin signal from insulin-producing cells (IPCs). Intriguingly, opto-activating IPCs elicits feeding inhibition for both protein and sugar, while silencing T1-DANs blocks this inhibition only for protein food. Elevating insulin signaling in T1-DANs or opto-activating these neurons is sufficient to mimic protein satiety. Furthermore, this signal is conveyed to local neurons of the protocerebral bridge (PB-LNs) and specifically suppresses protein intake. Therefore, our findings reveal that a brain-derived insulin signal encodes protein satiety and suppresses feeding behavior in a nutrient-specific manner, shedding light on the functional specificity of brain insulin signals in regulating behaviors. [Display omitted] •Insulin signaling in a pair of T1-DANs represents protein-specific satiety•In female flies, protein intake induces DILP2 release and activates T1-DANs•Opto-activating IPCs in the brain suppresses food intake of both sugar and protein•Downstream of IPCs, the T1-PB circuit specifically mediates protein satiety signal In this study, Li et al. identify a neural circuit in adult female fly brain that functions downstream of insulin-producing cells and selectively responds to the protein-intake-induced insulin signal. Through this circuit, such an insulin-encoded protein satiety signal suppresses feeding behavior, specific to protein intake.