title: Lkb1 controls brown adipose tissue growth and thermogenesis by regulating the intracellular localization of CRTC3.
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.
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.|College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Tizhong
authors.initials: T
authors.lastname: Shan
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.|Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Pengpeng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Qingyang
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Pengpeng
authors.initials: P
authors.lastname: Bi
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Yue
authors.affiliation: Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China.
authors.forename: Gongshe
authors.initials: G
authors.lastname: Yang
authors.affiliation: College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Yizhen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA.|Purdue University Center for Cancer Research, West Lafayette, Indiana 47907, USA.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.|Purdue University Center for Cancer Research, West Lafayette, Indiana 47907, USA.
authors.forename: Shihuan
authors.identifier: 0000-0001-9180-3180
authors.initials: S
authors.lastname: Kuang
mesh_terms: D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D052436:Adipose Tissue, White / Q000378:metabolism / Q000473:pathology; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D059305:Diet, High-Fat; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D057809:HEK293 Cells; D006801:Humans; D006965:Hyperplasia; D006984:Hypertrophy; D007333:Insulin Resistance; D019426:Integrases / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009765:Obesity; D009929:Organ Size; D009928:Organ Specificity; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D022722:Thermogenesis; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics
chemical_list: D052242:Adiponectin; D022782:CCAAT-Enhancer-Binding Protein-beta; C555318:CRTC3 protein, mouse; C545013:Cebpb protein, mouse; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase; C045073:Cre recombinase; D019426:Integrases; D005947:Glucose