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In animals, the brain regulates feeding behavior in response to local energy demands of peripheral tissues, which secrete orexigenic and anorexigenic hormones. Although skeletal muscle is a key peripheral tissue, it remains unknown whether muscle-secreted hormones regulate feeding. In  Drosophila , we found that  decapentaplegic  ( dpp ), the homolog of human bone morphogenetic proteins BMP2 and BMP4, is a muscle-secreted factor (a myokine) that is induced by nutrient sensing and that circulates and signals to the brain. Muscle-restricted dpp RNAi promotes foraging and feeding initiation, whereas  dpp  overexpression reduces it. This regulation of feeding by muscle-derived Dpp stems from modulation of brain  tyrosine hydroxylase  ( TH ) expression and dopamine biosynthesis. Consistently, Dpp receptor signaling in dopaminergic neurons regulates  TH  expression and feeding initiation via the downstream transcriptional repressor Schnurri. Moreover, pharmacologic modulation of TH activity rescues the changes in feeding initiation due to modulation of  dpp  expression in muscle. These findings indicate that muscle-to-brain endocrine signaling mediated by the myokine Dpp regulates feeding behavior.

Muscle-derived Dpp regulates feeding initiation via endocrine modulation of brain dopamine biosynthesis