title: Smad3 deficiency in mice protects against insulin resistance and obesity induced by a high-fat diet.
abstract: OBJECTIVE
  Obesity and associated pathologies are major global health problems. Transforming growth factor-β/Smad3 signaling has been implicated in various metabolic processes, including adipogenesis, insulin expression, and pancreatic β-cell function. However, the systemic effects of Smad3 deficiency on adiposity and insulin resistance in vivo remain elusive. This study investigated the effects of Smad3 deficiency on whole-body glucose and lipid homeostasis and its contribution to the development of obesity and type 2 diabetes.
  
  
  METHODS
  We compared various metabolic profiles of Smad3-knockout and wild-type mice. We also determined the mechanism by which Smad3 deficiency affects the expression of genes involved in adipogenesis and metabolism. Mice were then challenged with a high-fat diet to study the impact of Smad3 deficiency on the development of obesity and insulin resistance.
  
  
  RESULTS
  Smad3-knockout mice exhibited diminished adiposity with improved glucose tolerance and insulin sensitivity. Chromatin immunoprecipitation assay revealed that Smad3 deficiency increased CCAAT/enhancer-binding protein β-C/EBP homologous protein 10 interaction and exerted a differential regulation on proliferator-activated receptor β/δ and proliferator-activated receptor γ expression in adipocytes. Focused gene expression profiling revealed an altered expression of genes involved in adipogenesis, lipid accumulation, and fatty acid β-oxidation, indicative of altered adipose physiology. Despite reduced physical activity with no modification in food intake, these mutant mice were resistant to obesity and insulin resistance induced by a high-fat diet.
  
  
  CONCLUSIONS
  Smad3 is a multifaceted regulator in adipose physiology and the pathogenesis of obesity and type 2 diabetes, suggesting that Smad3 may be a potential target for the treatment of obesity and its associated disorders.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Chek Kun
authors.initials: CK
authors.lastname: Tan
authors.forename: Nicolas
authors.initials: N
authors.lastname: Leuenberger
authors.forename: Ming Jie
authors.initials: MJ
authors.lastname: Tan
authors.forename: Yew Wai
authors.initials: YW
authors.lastname: Yan
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Chen
authors.forename: Ravi
authors.initials: R
authors.lastname: Kambadur
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli
authors.forename: Nguan Soon
authors.initials: NS
authors.lastname: Tan
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism*; D001823:Body Composition / Q000502:physiology; D004032:Diet; D004041:Dietary Fats / Q000378:metabolism; D005227:Fatty Acids / Q000097:blood; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D018709:Statistics, Nonparametric
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D005227:Fatty Acids; D051900:Smad3 Protein