In this 2014 study, Yue Wang and colleagues looked at how leptin—a hormone that helps regulate hunger—is released from fat cells. They found that insulin plays a key role in triggering leptin release, not by turning on the gene, but by activating internal cell signaling pathways, especially the PI3K/Akt pathway.

Leptin isn’t just sitting in storage waiting to be released. Instead, it has to be continuously made and transported inside the cell before it can be secreted. When the researchers blocked protein production or this internal transport system, leptin release stopped—even in the presence of insulin. They also found that calcium is required for this process, but it doesn’t directly trigger leptin release. Instead, it helps insulin signaling work properly.

Importantly, in insulin-resistant mice, this system didn’t work as well, and leptin responses were impaired. This suggests that leptin is not the main driver of hunger on its own, but rather a downstream signal that reflects how well metabolism is working. When metabolic signaling is healthy, leptin helps communicate that the body is fed. When metabolism is impaired, that signal can break down—even if body fat is high.

https://www.researchgate.net/publication/259650147_Insulin-stimulated_leptin_secretion_requires_calcium_and_PI3KAkt_activation