title: Selective inactivation of c-Jun NH2-terminal kinase in adipose tissue protects against diet-induced obesity and improves insulin sensitivity in both liver and skeletal muscle in mice.
abstract: OBJECTIVE
  Obesity is associated with increased activation of the c-Jun NH(2)-terminal kinase (JNK) in several metabolic organs, including adipose tissue, liver, and skeletal muscle. In this study, we aimed to define the role of JNK activation in adipose tissue in the development of obesity-related insulin resistance.
  
  
  METHODS
  Transgenic mice with adipose tissue-specific overexpression of dominant-negative JNK (ap2-dn-JNK) under the transcriptional control of the aP2 gene promoter were generated and subjected to metabolic characterization together with the wild-type littermates.
  
  
  RESULTS
  On a high-fat diet (HFD), the ap2-dn-JNK mice displayed a marked suppression of both JNK1 and JNK2 activation in their adipose tissue, accompanied by a marked reduction in weight gain, fat mass, and size of the adipocytes. The transgenic mice were resistant to the deleterious impact of an HFD on systemic insulin sensitivity, glucose tolerance, and hepatic steatosis. Reduced hepatic gluconeogenesis was evident in in vivo and ex vivo studies and showed greater insulin-induced glucose uptake in skeletal muscles. These changes were accompanied by reduced macrophage infiltration in adipose tissue, decreased production of proinflammatory adipokines, and increased expression of adiponectin. Indirect calorimetry analysis showed that the transgenic mice had significant increases in oxygen consumption and reductions in respiration exchange rates compared with their wild-type littermates.
  
  
  CONCLUSIONS
  Selective suppression of JNK activation in adipose tissue alone is sufficient to counteract HFD-induced obesity and its associated metabolic dysregulations, in part through an increase in energy expenditure and a decrease in systemic inflammation.
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong.
authors.forename: Xinmei
authors.initials: X
authors.lastname: Zhang
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.forename: Sookja K
authors.initials: SK
authors.lastname: Chung
authors.forename: Justin H B
authors.initials: JH
authors.lastname: Cresser
authors.forename: Gary
authors.initials: G
authors.lastname: Sweeney
authors.forename: Rachel L C
authors.initials: RL
authors.lastname: Wong
authors.forename: Anning
authors.initials: A
authors.lastname: Lin
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D002153:Calorimetry, Indirect; D004032:Diet; D004041:Dietary Fats / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004041:Dietary Fats; D007328:Insulin; D048031:JNK Mitogen-Activated Protein Kinases