Metabolic Signalling

In a caloric deficit, circulating IGF-1 drops ~40% and leucine's mTORC1 signal weakens due to reduced Sestrin2 displacement. IGF-1 LR3—engineered to evade IGF-binding proteins—maintains receptor-level PI3K/Akt input independently of energy status, while leucine supplies a parallel, lysosome-anchored RAGULATOR/Rag GTPase signal. The two inputs converge on mTORC1-S6K1/4E-BP1 through mechanistically distinct but additive routes.