Insulin is a highly conserved hormone in evolution and plays a key role in various biological processes such as growth, development, and metabolism. In general, insulin signals represent high nutrition levels and are involved in the regulation of feeding behavior. However, it is not clear whether insulin signals can encode specific types of nutritional information and directly regulate feeding behavior by transmitting signals to specific neurons.

In a study published in Cell Reports on May 24, a research group led by Prof. LI Yan at the Institute of Biophysics of the Chinese Academy of Sciences reported a brain insulin signal that encodes protein satiety and its neural mechanism in regulating protein feeding behavior, revealing a new function of insulin signaling in the central nervous system.

The researchers performed a behavioral screen by knocking down insulin receptors and identified the direct downstream target of brain insulin-producing cells (IPCs) - tritocerebrum 1 (T1) dopamine neurons. Following protein satiety, the activity of T1 neurons increased significantly. Activating T1 neurons or increasing insulin signaling within them specifically inhibited protein feeding in flies, while inhibiting T1 neurons or reducing insulin signaling eliminated the feeding suppression effect after protein satiety.

Interestingly, activation of IPCs led to a decrease in protein and sugar intake in flies, whereas inhibition of T1 neurons selectively blocked the decrease in protein intake without affecting the decrease in sugar intake. This suggests that insulin signaling can represent satiety information for different types of nutrients, with T1 neurons specifically mediating protein satiety information.

Using approaches such as EM connectome mapping and in vivo calcium imaging, the researchers discovered the local neurons of the protocerebral bridge (PB-LNs) downstream of the T1 neurons. Similar to T1 neurons, inhibiting PB-LNs also blocked the feeding suppression effect after protein satiety. However, activation of PB-LNs no longer showed nutrient selectivity in inhibiting feeding behavior, indicating the integration of nutritional information from protein food.

This study demonstrates that insulin signaling in the central nervous system can encode high-protein nutritional information and participate in immediate and precise behavioral regulation through specific downstream neurons. In mammals, there are multiple insulin and insulin-like signals in the brain. These findings in flies provide important insights for studying the functions of insulin signaling in the mammalian central nervous system and its mechanisms in regulating feeding behavior.

Neural circuitry regulating feeding behavior through a brain-derived insulin signal encoding protein satiety. (Image by LI Yan's group)