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

Genes Dev. 2020 Jan 1;34(1-2):37-52. doi: 10.1101/gad.329110.119. Epub 2019 Dec 12.

Abstract

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.

Keywords: Dpp; Drosophila; dopamine; endocrine signaling; feeding behavior; foraging; myokine; skeletal muscle; tyrosine hydroxylase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / physiology
  • DNA-Binding Proteins / metabolism
  • Dopamine Agents / pharmacology
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / physiology
  • Drosophila / enzymology
  • Drosophila / genetics*
  • Drosophila / metabolism*
  • Drosophila Proteins / metabolism*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Feeding Behavior / physiology*
  • Levodopa / pharmacology
  • Monoiodotyrosine / pharmacology
  • Signal Transduction
  • Transcription Factors / metabolism
  • Tyrosine 3-Monooxygenase / genetics
  • Up-Regulation

Substances

  • 3-iodotyrosine
  • DNA-Binding Proteins
  • Dopamine Agents
  • Drosophila Proteins
  • Enzyme Inhibitors
  • Transcription Factors
  • dpp protein, Drosophila
  • shn protein, Drosophila
  • Levodopa
  • Tyrosine 3-Monooxygenase
  • Monoiodotyrosine