title: The stem cell factor/Kit signalling pathway regulates mitochondrial function and energy expenditure.
abstract: Cell growth is tightly coupled with mitochondrial biogenesis in order to maintain energy and organelle homeostasis. Receptor tyrosine kinase Kit and its ligand, stem cell factor (SCF), play a critical role in the growth and survival of multiple cell lineages. Here we report that the expression of SCF and Kit in adipose tissues is responsive to food availability and environmental temperature, and is altered in obese mice and human patients. Mice carrying a loss-of-function mutation in Kit develop obesity as a result of decreased energy expenditure. These phenotypes are associated with reduced PGC-1α expression and mitochondrial dysfunction in brown adipose tissue and skeletal muscle. We further demonstrate that SCF/Kit directly promotes Ppargc1a transcription and mitochondrial biogenesis. Blocking Kit signalling in mice decreases PGC-1α expression and thermogenesis, while overexpressing SCF systemically or specifically in brown adipose tissue increases thermogenesis and reduces weight gain. Collectively, these data provide mechanistic insight into the regulation of mitochondrial function by SCF/Kit signalling and lay a foundation for exploring SCF/Kit signalling as a therapeutic target for metabolic diseases.
authors.affiliation: 1] MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210061, China [2].
authors.forename: Zan
authors.initials: Z
authors.lastname: Huang
authors.affiliation: 1] MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210061, China [2] Section of Comparative Medicine, Yale University School of Medicine, PO BOX 208016, New Haven, Connecticut 06520-8016, USA [3].
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Ruan
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210061, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xian
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210061, China.
authors.forename: Weiqian
authors.initials: W
authors.lastname: Chen
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210061, China.
authors.forename: Shujun
authors.initials: S
authors.lastname: Jiang
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210061, China.
authors.forename: Anying
authors.initials: A
authors.lastname: Song
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210061, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210061, China.
authors.forename: Peiliang
authors.initials: P
authors.lastname: Shi
authors.affiliation: Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Gu
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210061, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D050154:Adiposity; D000818:Animals; D004734:Energy Metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D063269:Mitochondrial Turnover; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D009765:Obesity / Q000209:etiology* / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D019089:Stem Cell Factor / Q000378:metabolism*; D022722:Thermogenesis; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D019089:Stem Cell Factor; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit