title: Decreased secretion of adiponectin through its intracellular accumulation in adipose tissue during tobacco smoke exposure.
abstract: BACKGROUND
  Cigarette smoking is associated with an increased risk of type 2 diabetes mellitus (T2DM). Smokers exhibit low circulating levels of total adiponectin (ADPN) and high-molecular-weight (HMW) ADPN multimers. Blood concentrations of HMW ADPN multimers closely correlate with insulin sensitivity for handling glucose. How tobacco smoke exposure lowers blood levels of ADPN, however, has not been investigated. In the current study, we examined the effects of tobacco smoke exposure in vitro and in vivo on the intracellular and extracellular distribution of ADPN and its HMW multimers, as well as potential mechanisms.
  
  
  RESULTS
  We found that exposure of cultured adipocytes to tobacco smoke extract (TSE) suppressed total ADPN secretion, and TSE administration to mice lowered their plasma ADPN concentrations. Surprisingly, TSE caused intracellular accumulation of HMW ADPN in cultured adipocytes and in the adipose tissue of wild-type mice, while preferentially decreasing HMW ADPN in culture medium and in plasma. Importantly, we found that TSE up-regulated the ADPN retention chaperone ERp44, which colocalized with ADPN in the endoplasmic reticulum. In addition, TSE down-regulated DsbA-L, a factor for ADPN secretion.
  
  
  CONCLUSIONS
  Tobacco smoke exposure traps HMW ADPN intracellularly, thereby blocking its secretion. Our results provide a novel mechanism for hypoadiponectinemia, and may help to explain the increased risk of T2DM in smokers.
authors.affiliation: Section of Endocrinology, Diabetes & Metabolic Diseases, Temple University School of Medicine, Philadelphia, PA USA.
authors.forename: Mingzhen
authors.initials: M
authors.lastname: Li
authors.affiliation: Section of Endocrinology, Diabetes & Metabolic Diseases, Temple University School of Medicine, Philadelphia, PA USA.
authors.forename: Chunjun
authors.initials: C
authors.lastname: Li
authors.affiliation: Section of Endocrinology, Diabetes & Metabolic Diseases, Temple University School of Medicine, Philadelphia, PA USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Section of Endocrinology, Diabetes & Metabolic Diseases, Temple University School of Medicine, Philadelphia, PA USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Section of Endocrinology, Diabetes & Metabolic Diseases, Temple University School of Medicine, Philadelphia, PA USA.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Wu
authors.affiliation: The Metabolic Disease Hospital, Tianjin Medical University, Tianjin, China.
authors.forename: Demin
authors.initials: D
authors.lastname: Yu
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA.|Philadelphia Veterans Administration Medical Center, Philadelphia, PA USA.
authors.forename: Victoria P
authors.initials: VP
authors.lastname: Werth
authors.affiliation: Section of Endocrinology, Diabetes & Metabolic Diseases, Temple University School of Medicine, Philadelphia, PA USA.|Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Kevin Jon
authors.initials: KJ
authors.lastname: Williams
authors.affiliation: Section of Endocrinology, Diabetes & Metabolic Diseases, Temple University School of Medicine, Philadelphia, PA USA.|Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA.|Philadelphia Veterans Administration Medical Center, Philadelphia, PA USA.
authors.forename: Ming-Lin
authors.initials: ML
authors.lastname: Liu
keywords: Adipocytes; Adiponectin; Tobacco smoke