Activation of GCN2/ATF4 signals in amygdalar PKC-δ neurons promotes WAT browning under leucine deprivation

Nat Commun. 2020 Jun 5;11(1):2847. doi: 10.1038/s41467-020-16662-2.

Abstract

The browning of white adipose tissue (WAT) has got much attention for its potential beneficial effects on metabolic disorders, however, the nutritional factors and neuronal signals involved remain largely unknown. We sought to investigate whether WAT browning is stimulated by leucine deprivation, and whether the amino acid sensor, general control non-derepressible 2 (GCN2), in amygdalar protein kinase C-δ (PKC-δ) neurons contributes to this regulation. Our results show that leucine deficiency can induce WAT browning, which is unlikely to be caused by food intake, but is largely blocked by PKC-δ neuronal inhibition and amygdalar GCN2 deletion. Furthermore, GCN2 knockdown in amygdalar PKC-δ neurons blocks WAT browning, which is reversed by over-expression of amino acid responsive gene activating transcription factor 4 (ATF4), and is mediated by the activities of amygdalar PKC-δ neurons and the sympathetic nervous system. Our data demonstrate that GCN2/ATF4 can regulate WAT browning in amygdalar PKC-δ neurons under leucine deprivation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism*
  • Adipose Tissue, Brown / physiology
  • Adipose Tissue, White / innervation
  • Adipose Tissue, White / physiology*
  • Amygdala / cytology
  • Amygdala / physiology*
  • Animals
  • Gene Knockdown Techniques
  • Leucine / metabolism*
  • Lipolysis / physiology
  • Male
  • Mice
  • Mice, Knockout
  • Neurons / metabolism
  • Protein Kinase C-delta / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction / physiology
  • Stereotaxic Techniques
  • Sympathetic Nervous System / physiology
  • Thermogenesis / physiology

Substances

  • Atf4 protein, mouse
  • Activating Transcription Factor 4
  • Prkcd protein, mouse
  • Eif2ak4 protein, mouse
  • Protein Serine-Threonine Kinases
  • Protein Kinase C-delta
  • Leucine