title: c-Abl inhibition mitigates diet-induced obesity through improving insulin sensitivity of subcutaneous fat in mice.
abstract: High-energy diets are among the main causes of the global epidemic of metabolic disorders, including obesity and type 2 diabetes. The mechanisms of high-energy-diet-induced metabolic disorders are complex and largely unknown. The non-receptor tyrosine kinase c-Abl plays an important role in adipogenesis in vitro but its role in vivo in the regulation of metabolism is still elusive. Hence, we sought to address the role of c-Abl in diet-induced obesity and obesity-associated insulin resistance.
  
  
  
  The expression of c-Abl in different fat tissues from obese humans or mice fed a high-fat diet (HFD) were first analysed by western blotting and quantitative PCR. We employed conditional deletion of the c-Abl gene (also known as Abl1) in adipose tissue using Fabp4-Cre and 6-week-old mice were fed with either a chow diet (CD) or an HFD. Age-matched wild-type mice were treated with the c-Abl inhibitor nilotinib or with vehicle and exposed to either CD or HFD, followed by analysis of body mass, fat mass, glucose and insulin tolerance. Histological staining, ELISA and biochemical analysis were used to clarify details of changes in physiology and molecular signalling.
  
  
  
  c-Abl was highly expressed in subcutaneous fat from obese humans and HFD-induced obese mice. Conditional knockout of c-Abl in adipose tissue improved insulin sensitivity and mitigated HFD-induced body mass gain, hyperglycaemia and hyperinsulinaemia. Consistently, treatment with nilotinib significantly reduced fat mass and improved insulin sensitivity in HFD-fed mice. Further biochemical analyses suggested that c-Abl inhibition improved whole-body insulin sensitivity by reducing HFD-triggered insulin resistance and increasing adiponectin in subcutaneous fat.
  
  
  
  Our findings define a new biological role for c-Abl in the regulation of diet-induced obesity through improving insulin sensitivity of subcutaneous fat. This suggests it may become a novel therapeutic target in the treatment of metabolic disorders.
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing, 100101, China.|College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing, 100101, China.|Sino-Danish Center Neuroscience Program, University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Jian-Guang
authors.initials: JG
authors.lastname: Sun
authors.affiliation: Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Ji-Qiu
authors.initials: JQ
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.
authors.forename: Binhua
authors.initials: B
authors.lastname: Li
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
authors.affiliation: Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing, 100101, China. jinw@ioz.ac.cn.
authors.forename: Wanzhu
authors.initials: W
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing, 100101, China. zqyuan@ibp.ac.cn.|College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. zqyuan@ibp.ac.cn.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, China. zqyuan@ibp.ac.cn.
authors.forename: Zengqiang
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D002149:Energy Intake / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005951:Glucose Tolerance Test; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009765:Obesity / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use; D050151:Subcutaneous Fat / Q000187:drug effects / Q000378:metabolism*
chemical_list: D011743:Pyrimidines; D016315:Proto-Oncogene Proteins c-abl; C498826:nilotinib
keywords: Adiponectin; Insulin resistance; Nilotinib; Obesity; c-Abl