title: 4-hydroxynonenal causes impairment of human subcutaneous adipogenesis and induction of adipocyte insulin resistance.
abstract: Increased adipose production of 4-hydroxynonenal (4-HNE), a bioreactive aldehyde, directly correlates with obesity and insulin resistance. The aim of this study was to elucidate the impact of 4-HNE in mediating adipocyte differentiation and function in two metabolically distinct obese groups; the insulin sensitive (IS) and the insulin resistant (IR).
  
  
  
  Subcutaneous (SC) adipose tissues were obtained from eighteen clinically well characterized obese premenopausal women undergoing weight reduction surgery. Cellular distribution of 4-HNE in the form of protein adducts was determined by immunohistochemistry in addition to its effect on oxidative stress, cell growth, adipogenic capacity and insulin signaling in preadipocytes derived from the IS and IR participants.
  
  
  
  4-HNE was detected in the SC adipose tissue in different cell types with the highest level detected in adipocytes and blood vessels. Short and long-term in vitro treatment of SC preadipocytes with 4-HNE caused inhibition of their growth and increased production of reactive oxygen species (ROS) and antioxidant enzymes. Repeated 4-HNE treatment led to a greater reduction in the adipogenic capacity of preadipocytes from IS subjects compared to IR and caused dephosphorylation of IRS-1 and p70S6K while activating GSK3α/β and BAD, triggering an IR phenotype.
  
  
  
  These data suggest that 4-HNE-induced oxidative stress plays a role in the regulation of preadipocyte growth, differentiation and insulin signaling and may therefore contribute to adipose tissue metabolic dysfunction associated with insulin resistance.
authors.affiliation: Anti Doping Lab Qatar, Sports City, Doha, Qatar.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Elrayess
authors.affiliation: Anti Doping Lab Qatar, Sports City, Doha, Qatar; School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Shamma
authors.initials: S
authors.lastname: Almuraikhy
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Wael
authors.initials: W
authors.lastname: Kafienah
authors.affiliation: Anti Doping Lab Qatar, Sports City, Doha, Qatar.
authors.forename: Afnan
authors.initials: A
authors.lastname: Al-Menhali
authors.affiliation: Anti Doping Lab Qatar, Sports City, Doha, Qatar.
authors.forename: Fatima
authors.initials: F
authors.lastname: Al-Khelaifi
authors.affiliation: Bariatric and Metabolic Surgery, Hamad Medical Corporation, Doha, Qatar.
authors.forename: Moataz
authors.initials: M
authors.lastname: Bashah
authors.affiliation: Department of Pathology, Medical Faculty University of Zagreb, Clinical Hospital Centre Zagreb, Zagreb, Croatia.
authors.forename: Kamelija
authors.initials: K
authors.lastname: Zarkovic
authors.affiliation: Laboratory for Oxidative Stress, Department of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
authors.forename: Neven
authors.initials: N
authors.lastname: Zarkovic
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Waeg
authors.affiliation: Anti Doping Lab Qatar, Sports City, Doha, Qatar.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alsayrafi
authors.affiliation: Anti Doping Lab Qatar, Sports City, Doha, Qatar. Electronic address: mjaganjac@adlqatar.qa.
authors.forename: Morana
authors.initials: M
authors.lastname: Jaganjac
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050156:Adipogenesis / Q000187:drug effects*; D000328:Adult; D000447:Aldehydes / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D051379:Mice; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000447:Aldehydes; D017382:Reactive Oxygen Species; C027576:4-hydroxy-2-nonenal
keywords: 4-hydroxynonenal; Adipogenesis; Insulin resistance; Insulin sensitivity; Obesity preadipocytes; Redox homeostasis; Subcutaneous fat