title: The ghrelin O-acyltransferase-ghrelin system reduces TNF-α-induced apoptosis and autophagy in human visceral adipocytes.
abstract: OBJECTIVE
  Proinflammatory and proapoptotic cytokines such as TNF-α are upregulated in human obesity. We evaluated the association between ghrelin isoforms (acylated and desacyl ghrelin) and TNF-α in obesity and obesity-associated type 2 diabetes, as well as the potential role of ghrelin in the control of apoptosis and autophagy in human adipocytes.
  
  
  METHODS
  Plasma concentrations of the ghrelin isoforms and TNF-α were measured in 194 participants. Ghrelin and ghrelin O-acyltransferase (GOAT) levels were analysed by western-blot, immunohistochemistry and real-time PCR in 53 biopsies of human omental adipose tissue. We also determined the effect of acylated and desacyl ghrelin (10 to 1,000 pmol/l) on TNF-α-induced apoptosis and autophagy-related molecules in omental adipocytes.
  
  
  RESULTS
  Circulating concentrations of acylated ghrelin and TNF-α were increased, whereas desacyl ghrelin levels were decreased in obesity-associated type 2 diabetes. Ghrelin and GOAT were produced in omental and subcutaneous adipose tissue. Visceral adipose tissue from obese patients with type 2 diabetes showed higher levels of GOAT, increased adipocyte apoptosis and increased expression of the autophagy-related genes ATG5, BECN1 and ATG7. In differentiating human omental adipocytes, incubation with acylated and desacyl ghrelin reduced TNF-α-induced activation of caspase-8 and caspase-3, and cell death. In addition, acylated ghrelin reduced the basal expression of the autophagy-related genes ATG5 and ATG7, while desacyl ghrelin inhibited the TNF-α-induced increase of ATG5, BECN1 and ATG7 expression.
  
  
  CONCLUSIONS
  Apoptosis and autophagy are upregulated in human visceral adipose tissue of patients with type 2 diabetes. Acylated and desacyl ghrelin reduce TNF-α-induced apoptosis and autophagy in human visceral adipocytes.
authors.affiliation: Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez
authors.forename: J
authors.initials: J
authors.lastname: Gómez-Ambrosi
authors.forename: V
authors.initials: V
authors.lastname: Catalán
authors.forename: F
authors.initials: F
authors.lastname: Rotellar
authors.forename: V
authors.initials: V
authors.lastname: Valentí
authors.forename: C
authors.initials: C
authors.lastname: Silva
authors.forename: C
authors.initials: C
authors.lastname: Mugueta
authors.forename: M R
authors.initials: MR
authors.lastname: Pulido
authors.forename: R
authors.initials: R
authors.lastname: Vázquez
authors.forename: J
authors.initials: J
authors.lastname: Salvador
authors.forename: M M
authors.initials: MM
authors.lastname: Malagón
authors.forename: I
authors.initials: I
authors.lastname: Colina
authors.forename: G
authors.initials: G
authors.lastname: Frühbeck
mesh_terms: D000215:Acylation / Q000502:physiology; D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000502:physiology*; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005260:Female; D054439:Ghrelin / Q000097:blood* / Q000235:genetics; D006801:Humans; D050152:Intra-Abdominal Fat / Q000166:cytology / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism; D009852:Omentum / Q000166:cytology / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
chemical_list: D054439:Ghrelin; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C422650:ghrelin, des-n-octanoyl; D000217:Acyltransferases; C542776:MBOAT4 protein, human