title: Decreased adiponectin links elevated adipose tissue autophagy with adipocyte endocrine dysfunction in obesity.
abstract: Adipose tissue (AT) autophagy gene expression is elevated in human obesity, correlating with increased metabolic risk, but mechanistic links between the two remain unclear. Thus, the objective of this study was to assess whether elevated autophagy may cause AT endocrine dysfunction, emphasizing the putative role of adiponectin in fat-liver endocrine communication.
  
  
  
  We utilized a large (N=186) human AT biobank to assess clinical associations between human visceral AT autophagy genes, adiponectin and leptin, by multivariate models. A broader view of adipocytokines association with elevated autophagy was assessed using adipocytokine array. Finally, to establish causality, ex vivo studies utilizing a murine AT-hepatocyte cell line co-culture system was used.
  
  
  
  Circulating high-molecular-weight adiponectin and leptin levels were associated with human omental-AT expression of ATG5 mRNA, associations that remained significant (β=-0.197, P=0.011; β=0.267, P<0.001, respectively) in a multivariate model adjusted for age, sex, body mass index and interleukin-6 (IL-6). A similar association was observed with omental-AT LC3A mRNA levels. Bafilomycin-A1 (Baf A) pretreatment of AT explants from high-fat-fed (HFF) mice had no effect on the secretion of some AT-derived endocrine factors, but partially or fully reversed obesity-related changes in secretion of a subset of adipocytokines by >30%, including the obesity-associated upregulation of IL-6, vascular endothelial growth factor, tumor necrosis factor alpha (TNFα) and certain insulin-like growth factor-binding proteins, and the HFF-induced downregulated secretion of IL-10 and adiponectin. Similarly, decreased adiponectin and increased leptin secretion from cultured adipocytes stimulated with TNFα+IL-1β was partially reversed by small interfering RNA-mediated knockdown of ATG7. AT explants from HFF mice co-cultured with Hepa1c hepatoma cells impaired insulin-induced Akt and GSK3 phosphorylation. This effect was significantly reversed by pretreating explants with Baf A, but not if adiponectin was immunodepleted from the conditioned media.
  
  
  
  Reduced secretion of adiponectin may link obesity-associated elevated AT autophagy/lysosomal activity with adipose endocrine dysfunction.
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Slutsky
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Vatarescu
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Haim
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Goldstein
authors.affiliation: Soroka Academic Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: B
authors.initials: B
authors.lastname: Kirshtein
authors.affiliation: Soroka Academic Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Harman-Boehm
authors.affiliation: Department of Epidemiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Gepner
authors.affiliation: Department of Epidemiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Shai
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Bashan
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Blüher
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Rudich
mesh_terms: D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D052242:Adiponectin / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001343:Autophagy; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004702:Endocrine Glands / Q000473:pathology*; D004700:Endocrine System Diseases / Q000473:pathology*; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D052242:Adiponectin; D012333:RNA, Messenger; D014157:Transcription Factors