biostudies-literatureRobles-Murguia MNICHD NIH HHSNIA NIH HHSGlenn Foundation for Medical ResearchNational Institute on Aging of the National Institutes of HealthAmerican Federation for Aging ResearchAmerican Parkinson Disease AssociationHartwell FoundationALSACEllison Medical Foundation37-52https://www.ebi.ac.uk/biostudies/studies/S-EPMC6938663biostudies-literatureUnknown34(1-2)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 <i>Drosophila</i>, we found that <i>decapentaplegic</i> (<i>dpp</i>), 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 <i>dpp</i> overexpression reduces it. This regulation of feeding by muscle-derived Dpp stems from modulation of brain <i>tyrosine hydroxylase</i> (<i>TH</i>) expression and dopamine biosynthesis. Consistently, Dpp receptor signaling in dopaminergic neurons regulates <i>TH</i> 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 <i>dpp</i> expression in muscle. These findings indicate that muscle-to-brain endocrine signaling mediated by the myokine Dpp regulates feeding behavior.Genes & developmentMuscle-derived Dpp regulates feeding initiation via endocrine modulation of brain dopamine biosynthesis.PMC6938663U54 HD083211R56 AG063806R01AG055532R56AG063806R01 AG055532Finkelstein DFan YRao DXu BDemontis FRobles-Murguia MfalseMuscle-derived Dpp regulates feeding initiation via endocrine modulation of brain dopamine biosynthesis.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 <i>Drosophila</i>, we found that <i>decapentaplegic</i> (<i>dpp</i>), 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 <i>dpp</i> overexpression reduces it. This regulation of feeding by muscle-derived Dpp stems from modulation of brain <i>tyrosine hydroxylase</i> (<i>TH</i>) expression and dopamine biosynthesis. Consistently, Dpp receptor signaling in dopaminergic neurons regulates <i>TH</i> 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 <i>dpp</i> expression in muscle. These findings indicate that muscle-to-brain endocrine signaling mediated by the myokine Dpp regulates feeding behavior.2020-01-01T00:00:00Z2020 Jan2024-02-15T17:23:05.498Z2020-07-04T07:18:46ZS-EPMC69386633183162810.1101/gad.329110.119