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

Cell Metab. 2018 Mar 6;27(3):616-629.e4. doi: 10.1016/j.cmet.2018.01.018.

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 (Lkb1BKO) 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 Lkb1BKO 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 Lkb1BKO 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.

Keywords: adaptive thermogenesis; brown adipocyte; electron transport chain; mitochondria; mtDNA; obesity; proteome imbalance.

Publication types

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

MeSH terms

  • Adipocytes, Brown / metabolism*
  • Adipose Tissue, Brown / metabolism*
  • Adiposity
  • Animals
  • DNA-Binding Proteins / metabolism
  • Diet, High-Fat
  • Electron Transport
  • Liver / metabolism
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • Mitochondrial Membranes / metabolism*
  • Mitochondrial Proteins / metabolism
  • Oxygen / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteome / metabolism*
  • Signal Transduction
  • Thermogenesis
  • Transcription Factors / metabolism
  • Triglycerides / metabolism

Substances

  • DNA-Binding Proteins
  • Mitochondrial Proteins
  • Proteome
  • Transcription Factors
  • Triglycerides
  • mitochondrial transcription factor A
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Oxygen