The FAT expandability (FATe) Project: Biomarkers to determine the limit of expansion and the complications of obesity

Abstract

BackgroundObesity is an excessive accumulation of fat frequently, but not always, associated with health problems, mainly type 2 diabetes and cardiovascular disease. During a positive energy balance, as caused by excessive intake or sedentary lifestyle, subcutaneous adipose tissue expands and accumulates lipids as triglycerides. However, the amount of adipose tissue per se is unlikely to be the factor linking obesity and metabolic complications. The expandability hypothesis states that, if this positive energy balance is prolonged, a point is eventually reached where subcutaneous adipose tissue can not further expand and energy surplus no longer can be safely stored. Once the limit on storage capacity has been exceeded, the dietary lipids start spilling and accumulate ectopically in other organs (omentum, liver, muscle, pancreas) forming lipid byproducts toxic to cells.Methods/DesignFATe is a multidisciplinary clinical project aimed to fill gaps that still exist in the expandability hypothesis. Imaging techniques (CT-scan), metabolomics, and transcriptomics will be used to identify the factors that set the limit expansion of subcutaneous adipose tissue in a cohort of caucasian individuals with varying degrees of adiposity. Subsequently, a set of biomarkers that inform the individual limits of expandability will be developed using computational and mathematical modeling. A different validation cohort will be used to minimize the risk of false positive rates and increase biomarkers' predictive performance.DiscussionThe work proposed here will render a clinically useful screening method to predict which obese individuals will develop metabolic derangements, specially diabetes and cardiovascular disease. This study will also provide mechanistic evidence that promoting subcutaneous fat expansion might be a suitable therapy to reduce metabolic complications associated with positive energy balance characteristic of Westernized societies.

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“…Subcutaneous abdominal adipose tissue from subjects undergoing elective laparoscopic surgery was used to obtain human mesenchymal stem cells (hMSCs) (27). All donors signed the written consent, and the study was approved by the local Institutional Review Board (CEIC‐A) and the Ethics Committee of the University of Navarra.…”

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“…The adipose tissue biopsies were obtained during elective surgeries (bariatric surgery, cholecystectomy or hernia repair) from the visceral (omental) depots . The biopsies were washed, vascular and connective tissue removed, and subsequently stored at −80°C in cryopreservation vials.…”

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“…Fresh plasma was donated by 17 individuals free of chronic or acute diseases. The AT biopsies were obtained during elective surgeries (bariatric surgery, cholecystectomy, or hernia repair) from the abdominal subcutaneous or visceral (omental) depots [22]. The biopsies were washed, devoid of vascular and connective tissue, and subsequently stored at − 80°C in cryopreservation vials.…”

“…Under obesogenic conditions the AT expands, as the accumulation of triglycerides in the AT is a safe way to store energy surplus. However, when adipose tissue growth exceeds a certain limit, metabolic complications may develop [22]. Some of those complications stem from the ectopic deposition of lipids in tissues such as the muscle, liver, or the omentum [13].…”