Excess visceral adiposity induces alterations in mitochondrial function and energy metabolism in esophageal adenocarcinoma

Abstract

BackgroundVisceral 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.MethodsAdipose 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.ResultsACM 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.ConclusionThis 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.

Positively increased visceral adiposity index in hyperuricemia free of metabolic syndrome

“…New founding was that Visceral fat, not subcutaneous depot, exhibited greater expression of proinflammatory, oxidative stress-related, hypoxia-induced, and proangiogenic genes; increased activated macrophage populations; and had a higher capacity for cytokine production ex vivo; thus providing clinical evidence that visceral microenvironment play key important role in atherosclerotic vascular disease [ 31 ]. Excess visceral adiposity induces alterations in mitochondrial function and energy metabolism in tumor [ 32 ], and correlated with the expression of genes related to inflammation and oxidative stress in peripheral blood cells [ 31 ]. Visceral fat adiposity was associated with sub-clinical inflammation and increased oxidative stress [ 33 ].…”

Vitamin C modulates the metabolic and cytokine profiles, alleviates hepatic endoplasmic reticulum stress, and increases the life span of Gulo−/− mice

“…In contrast, hepatic mitochondrial size correlated inversely with specific long chain phosphatidylcholines (PC aa C42:4 and PC aa C42:6), body weight and visceral fat weight. Interestingly, it has recently been reported that excess visceral adiposity is significantly associated with mitochondrial size and dysfunction [ 46 ]. Spermine and spermidine are known to modulate hepatic mitochondrial metabolism [ 47 ].…”

Emerging Concepts Linking Obesity with the Hallmarks of Cancer

“…Evasion of apoptosis, proliferation, and invasion have also been linked with altered mitochondrial function [118]. Treatment of oesophageal adenocarcinoma cell lines with adipose-conditioned media from obese patients with oesophageal cancer led to increased mitochondrial mass and membrane potential, differential expression of metabolites, and a shift to glycolysis [119].…”