Proteome Imbalance of Mitochondrial Electron Transport Chain in Brown Adipocytes Leads to Metabolic Benefits

Ruchi Masand, Esther Paulo, Dongmei Wu, Yangmeng Wang, Danielle L. Swaney, David Jimenez-Morales, Nevan J. Krogan, Biao Wang

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Brown adipose tissue (BAT) thermogenesis is critical for thermoregulation and contributes to total energy expenditure. However, whether BAT has non-thermogenic functions is largely unknown. Here, we describe that BAT-specific liver kinase b1 knockout (Lkb1 BKO ) mice exhibited impaired BAT mitochondrial respiration and thermogenesis but reduced adiposity and liver triglyceride accumulation under high-fat-diet feeding at room temperature. Importantly, these metabolic benefits were also present in Lkb1 BKO mice at thermoneutrality, where BAT thermogenesis was not required. Mechanistically, decreased mRNA levels of mtDNA-encoded electron transport chain (ETC) subunits and ETC proteome imbalance led to defective BAT mitochondrial respiration in Lkb1 BKO mice. Furthermore, reducing mtDNA gene expression directly in BAT by removing mitochondrial transcription factor A (Tfam) in BAT also showed ETC proteome imbalance and the trade-off between BAT thermogenesis and systemic metabolism at room temperature and thermoneutrality. Collectively, our data demonstrate that ETC proteome imbalance in BAT regulates systemic metabolism independently of thermogenesis. Masand and Paulo et al. demonstrate that Lkb1 and Tfam regulate mtDNA-encoded ETC gene expression, and their deficiencies in BAT lead to ETC proteome imbalance, a mismatch between proportional ETC complexes. This ETC proteome imbalance locally in BAT can cause systemic adaptive responses, which ultimately result in metabolic fitness.

Original languageEnglish
Pages (from-to)616-629.e4
JournalCell Metabolism
Volume27
Issue number3
DOIs
StatePublished - 6 Mar 2018
Externally publishedYes

Keywords

  • adaptive thermogenesis
  • brown adipocyte
  • electron transport chain
  • mitochondria
  • mtDNA
  • obesity
  • proteome imbalance

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