title: Excess visceral adiposity induces alterations in mitochondrial function and energy metabolism in esophageal adenocarcinoma.
abstract: BACKGROUND
  Visceral obesity has a strong association with both the incidence and mortality of esophageal adenocarcinoma (EAC). Alterations in mitochondrial function and energy metabolism is an emerging hallmark of cancer, however, the potential role that obesity plays in driving these alterations in EAC is currently unknown.
  
  
  METHODS
  Adipose conditioned media (ACM) was prepared from visceral adipose tissue taken from computed tomography-determined viscerally-obese and non-obese EAC patients. Mitochondrial function in EAC cell lines was assessed using fluorescent probes, mitochondrial gene expression was assessed using qPCR-based gene arrays and intracellular ATP levels were determined using a luminescence-based kit. Glycolysis and oxidative phosphophorylation was measured using Seahorse XF technology and metabolomic analysis was performed using 1H NMR. Expression of metabolic markers was assessed in EAC tumor biopsies by qPCR.
  
  
  RESULTS
  ACM from obese EAC patients significantly increased mitochondrial mass and mitochondrial membrane potential in EAC cells, which was significantly associated with visceral fat area, and was coupled with a significant decrease in reactive oxygen species. This mitochondrial dysfunction was accompanied by altered expression of 19 mitochondrial-associated genes and significantly reduced intracellular ATP levels. ACM from obese EAC patients induced a metabolic shift to glycolysis in EAC cells, which was coupled with significantly increased sensitivity to the glycolytic inhibitor 2-deoxyglucose. Metabolomic profiling demonstrated an altered glycolysis and amino acid-related signature in ACM from obese patients. In EAC tumors, expression of the glycolytic marker PKM2 was significantly positively associated with obesity.
  
  
  CONCLUSIONS
  This study demonstrates for the first time that ACM from viscerally-obese EAC patients elicits an altered metabolic profile and can drive mitochondrial dysfunction and altered energy metabolism in EAC cells in vitro. In vivo, in EAC patient tumors, expression of the glycolytic enzyme PKM2 is positively associated with obesity.
authors.forename: Niamh
authors.initials: N
authors.lastname: Lynam-Lennon
authors.forename: Ruth
authors.initials: R
authors.lastname: Connaughton
authors.forename: Eibhlin
authors.initials: E
authors.lastname: Carr
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Mongan
authors.forename: Naoimh J
authors.initials: NJ
authors.lastname: O'Farrell
authors.forename: Richard K
authors.initials: RK
authors.lastname: Porter
authors.forename: Lorraine
authors.initials: L
authors.lastname: Brennan
authors.forename: Graham P
authors.initials: GP
authors.lastname: Pidgeon
authors.forename: Joanne
authors.initials: J
authors.lastname: Lysaght
authors.forename: John V
authors.initials: JV
authors.lastname: Reynolds
authors.affiliation: Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland. osullij4@tcd.ie.
authors.forename: Jacintha
authors.initials: J
authors.lastname: O'Sullivan
mesh_terms: D000230:Adenocarcinoma / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000368:Aged; D000963:Antimetabolites / Q000494:pharmacology; D015992:Body Mass Index; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D003847:Deoxyglucose / Q000494:pharmacology; D004734:Energy Metabolism; D004938:Esophageal Neoplasms / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D005260:Female; D015870:Gene Expression; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D050152:Intra-Abdominal Fat / Q000000981:diagnostic imaging / Q000502:physiology*; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000235:genetics; D055442:Metabolome; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000502:physiology*; D056128:Obesity, Abdominal / Q000150:complications / Q000503:physiopathology*; D011859:Radiography; D017382:Reactive Oxygen Species / Q000378:metabolism; D013963:Thyroid Hormones / Q000235:genetics; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000255:Adenosine Triphosphate; D000963:Antimetabolites; D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D003847:Deoxyglucose; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins