Lkb1 Controls Brown Adipose Tissue Growth and Thermogenesis by Regulating the Intracellular Localization of CRTC3

Nat Commun. 2016 Jul 27;7:12205. doi: 10.1038/ncomms12205.

Abstract

Brown adipose tissue (BAT) dissipates energy through Ucp1-mediated uncoupled respiration and its activation may represent a therapeutic strategy to combat obesity. Here we show that Lkb1 controls BAT expansion and UCP1 expression in mice. We generate adipocyte-specific Lkb1 knockout mice and show that, compared with wild-type littermates, these mice exhibit elevated UCP1 expression in BAT and subcutaneous white adipose tissue, have increased BAT mass and higher energy expenditure. Consequently, KO mice have improved glucose tolerance and insulin sensitivity, and are more resistant to high-fat diet (HFD)-induced obesity. Deletion of Lkb1 results in a cytoplasm to nuclear translocation of CRTC3 in brown adipocytes, where it recruits C/EBPβ to enhance Ucp1 transcription. In parallel, the absence of Lkb1 also suppresses AMPK activity, leading to activation of the mTOR signalling pathway and subsequent BAT expansion. These data suggest that inhibition of Lkb1 or its downstream signalling in adipocytes could be a novel strategy to increase energy expenditure in the context of obesity, diabetes and other metabolic diseases.

Publication types

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

MeSH terms

  • Adenylate Kinase / metabolism
  • Adipocytes / metabolism
  • Adiponectin / metabolism
  • Adipose Tissue, Brown / growth & development*
  • Adipose Tissue, Brown / metabolism*
  • Adipose Tissue, Brown / pathology
  • Adipose Tissue, White / metabolism
  • Adipose Tissue, White / pathology
  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Cell Nucleus / metabolism
  • Diet, High-Fat
  • Gene Deletion
  • Gene Expression Profiling
  • Glucose / metabolism
  • Glucose Tolerance Test
  • HEK293 Cells
  • Humans
  • Hyperplasia
  • Hypertrophy
  • Insulin Resistance
  • Integrases / metabolism
  • Intracellular Space / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Obesity
  • Organ Size
  • Organ Specificity
  • Protein Binding
  • Protein Transport
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Thermogenesis*
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Up-Regulation / genetics

Substances

  • Adiponectin
  • CCAAT-Enhancer-Binding Protein-beta
  • CRTC3 protein, mouse
  • Cebpb protein, mouse
  • Transcription Factors
  • Stk11 protein, mouse
  • TOR Serine-Threonine Kinases
  • Protein-Serine-Threonine Kinases
  • Adenylate Kinase
  • Cre recombinase
  • Integrases
  • Glucose