Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism

Cell Rep. 2021 Sep 21;36(12):109742. doi: 10.1016/j.celrep.2021.109742.


Cold-induced thermogenesis in endotherms demands adaptive thermogenesis fueled by mitochondrial respiration and Ucp1-mediated uncoupling in multilocular brown adipocytes (BAs). However, dietary regulation of thermogenesis in BAs isn't fully understood. Here, we describe that the deficiency of Leucine-rich pentatricopeptide repeat containing-protein (Lrpprc) in BAs reduces mtDNA-encoded ETC gene expression, causes ETC proteome imbalance, and abolishes the mitochondria-fueled thermogenesis. BA-specific Lrpprc knockout mice are cold resistant in a 4°C cold-tolerance test in the presence of food, which is accompanied by the activation of transcription factor 4 (ATF4) and proteome turnover in BAs. ATF4 activation genetically by BA-specific ATF4 overexpression or physiologically by a low-protein diet feeding can improve cold tolerance in wild-type and Ucp1 knockout mice. Furthermore, ATF4 activation in BAs improves systemic metabolism in obesogenic environment regardless of Ucp1's action. Therefore, our study reveals a diet-dependent but Ucp1-independent thermogenic mechanism in BAs that is relevant to systemic thermoregulation and energy homeostasis.

Keywords: ATF4; brown adipocyte; thermogenesis.

Publication types

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

MeSH terms

  • Activating Transcription Factor 4 / deficiency
  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism*
  • Adipose Tissue, Brown / metabolism*
  • Animals
  • Body Weight
  • Cold Temperature
  • Diet / veterinary
  • Energy Metabolism
  • Female
  • Iodide Peroxidase / genetics
  • Iodide Peroxidase / metabolism
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Neoplasm Proteins / deficiency
  • Neoplasm Proteins / genetics
  • Thermogenesis* / genetics
  • Uncoupling Protein 1 / deficiency
  • Uncoupling Protein 1 / genetics
  • Uncoupling Protein 1 / metabolism


  • Atf4 protein, mouse
  • Lrpprc protein, mouse
  • Neoplasm Proteins
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Activating Transcription Factor 4
  • iodothyronine deiodinase type II
  • Iodide Peroxidase