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

Cardiovascular Diabetology

Jose M Arbones-Mainar⁴  Javier Lagos³  Jose Maria Artigas⁵  Alejandro Sanz-Paris¹  Maria Pilar Garcia-Sobreviela²  Carmen Ortega⁶  Luisa Calvo-Ruata⁶  Pilar Calmarza⁶  Yolanda Gonzalez-Irazabal⁶  Beatriz Garcia-Rodriguez⁶  Monica Valero³  Elena Torres-Perez² 

[1] Servicio de Endocrinología y Nutrición, Hospital Universitario Miguel Servet, Zaragoza, Spain;Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain;Unidad de Cirugía, Hospital Royo Villanova, Zaragoza, Spain;Centro de Investigación Biomédica en Red Fisiopatología Obesidad y Nutrición (CIBERObn), Instituto Salud Carlos III, Madrid, Spain;Servicio de Radiodiagnóstico, Hospital Universitario Miguel Servet, Zaragoza, Spain;Servicio de Bioquímica Clínica, Hospital Universitario Miguel Servet, Zaragoza, Spain

关键词: Metabolomics;    CT-scan;    Type 2 diabetes;    Biomarkers;    Adipose tissue;   

Others  :  1177360
DOI  :  10.1186/s12933-015-0203-6

 received in 2015-02-17, accepted in 2015-03-06,  发布年份 2015

【 摘 要 】

Background

Obesity 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/Design

FATe 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.

Discussion

The 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.

【 授权许可】

   
2015 Torres-Perez et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Haffner SM: Relationship of Metabolic Risk Factors and Development of Cardiovascular Disease and Diabetes. Obesity 2006, 14:121S-7.
• [2]Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey J, et al.: Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 2009, 373:1083-96.
• [3]Berrington de Gonzalez A, Hartge P, Cerhan JR, Flint AJ, Hannan L, MacInnis RJ, et al.: Body-Mass Index and Mortality among 1.46 Million White Adults. N Engl J Med 2010, 363:2211-9.
• [4]Louie SM, Roberts LS, Nomura DK: Mechanisms linking obesity and cancer. Biochim Biophys Acta 1831, 2013:1499-508.
• [5]Karelis AD, Faraj M, Bastard J-P, St-Pierre DH, Brochu M, Prud’homme D, et al.: The Metabolically Healthy but Obese Individual Presents a Favorable Inflammation Profile. J Clin Endocrinol Metab 2005, 90:4145-50.
• [6]Stefan N, Kantartzis K, Machann J, Schick F, Thamer C, Rittig K, et al.: Identification and characterization of metabolically benign obesity in humans. Arch Intern Med 2008, 168:1609-16.
• [7]Wildman RP, Muntner P, Reynolds K, McGinn AP, Rajpathak S, Wylie-Rosett J, et al.: The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999–2004). Arch Intern Med 2008, 168:1617-24.
• [8]Hamer M, Stamatakis E: Metabolically Healthy Obesity and Risk of All-Cause and Cardiovascular Disease Mortality. J Clin Endocrinol Metab 2012, 97(7):2482-8.
• [9]Shea JL, Randell EW, Sun G: The prevalence of metabolically healthy obese subjects defined by BMI and dual-energy X-ray absorptiometry. Obesity 2011, 19:624-30.
• [10]Cristancho AG, Lazar MA: Forming functional fat: a growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol 2011, 12:722-34.
• [11]Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, et al.: Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002, 13:4279-95.
• [12]Sethi JK: Activatin’ human adipose progenitors in obesity. Diabetes 2010, 59:2354-7.
• [13]Nishimura S, Manabe I, Nagasaki M, Hosoya Y, Yamashita H, Fujita H, et al.: Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells, and blood vessels. Diabetes 2007, 56:1517-26.
• [14]Gray SL, Vidal-Puig AJ: Adipose Tissue Expandability in the Maintenance of Metabolic Homeostasis. Nutr Rev 2007, 65:S7-12.
• [15]Laclaustra M, Corella D, Ordovas JM: Metabolic syndrome pathophysiology: the role of adipose tissue. Nutr Metab Cardiovasc Dis 2007, 17:125-39.
• [16]Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al.: Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003, 112:1821-30.
• [17]Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, et al.: Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 2005, 46:2347-55.
• [18]Wu D, Molofsky AB, Liang H-E, Ricardo-Gonzalez RR, Jouihan HA, Bando JK, et al.: Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 2011, 332:243-7.
• [19]Lee Y-H, Chen S-Y, Wiesner RJ, Huang Y-F: Simple flow cytometric method used to assess lipid accumulation in fat cells. J Lipid Res 2004, 45(6):1162-7.
• [20]Miranville A, Heeschen C, Sengenès C, Curat CA, Busse R, Bouloumié A: Improvement of postnatal neovascularization by human adipose tissue-derived stem cells. Circulation 2004, 110:349-55.
• [21]Boulet N, Estève D, Bouloumié A, Galitzky J: Cellular heterogeneity in superficial and deep subcutaneous adipose tissues in overweight patients. J Physiol Biochem 2013, 69:575-83.
• [22]Folch J, Lees M, Sloane-Stanley GH: A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 1957, 226:497-509.
• [23]Krotkiewski M, Björntorp P, Sjöström L, Smith U: Impact of obesity on metabolism in men and women. Importance of regional adipose tissue distribution. J Clin Invest 1983, 72:1150-62.
• [24]Janssen I, Katzmarzyk PT, Ross R: Waist circumference and not body mass index explains obesity-related health risk. Am J Clin Nutr 2004, 79(3):379-84.
• [25]Lin H-H, Lee J-K, Yang C-Y, Lien Y-C, Huang J-W, Wu C-K: Accumulation of epicardial fat rather than visceral fat is an independent risk factor for left ventricular diastolic dysfunction in patients undergoing peritoneal dialysis. Cardiovasc Diabetol 2013, 12:127. BioMed Central Full Text
• [26]Pinnick KE, Nicholson G, Manolopoulos KN, McQuaid SE, Valet P, Frayn KN, et al.: Distinct developmental profile of lower-body adipose tissue defines resistance against obesity-associated metabolic complications. Diabetes 2014, 63:3785-97.
• [27]Seidell JC, Bakker CJ, van der Kooy K: Imaging techniques for measuring adipose-tissue distribution--a comparison between computed tomography and 1.5-T magnetic resonance. Am J Clin Nutr 1990, 51(6):953-7.
• [28]Shen W, Punyanitya M, Wang Z, Gallagher D, St-Onge M-P, Albu J, et al.: Visceral adipose tissue: relations between single-slice areas and total volume. Am J Clin Nutr 2004, 80:271-8.
• [29]Sottier D, Petit J-M, Guiu S, Hamza S, Benhamiche H, Hillon P, et al.: Quantification of the visceral and subcutaneous fat by computed tomography: interobserver correlation of a single slice technique. Diagn Interv Imaging 2013, 94:879-84.
• [30]Biomarkers Definitions Working Group: Biomarkers and surrogate endpoints: preferred definitions and conceptual framework Clin Pharmacol Ther 2001, 69:89-95.
• [31]Montastier E, Villa-Vialaneix N, Caspar-Bauguil S, Hlavaty P, Tvrzicka E, Gonzalez I, et al.: System model network for adipose tissue signatures related to weight changes in response to calorie restriction and subsequent weight maintenance. PLoS Comput Biol 2015., 11Article ID e1004047
• [32]Wang Z, Gerstein M, Snyder M: RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 2009, 10:57-63.
• [33]Han H, Jiang X: Disease Biomarker Query from RNA-Seq Data. Cancer Inform 2014, 13(Suppl 1):81-94.
• [34]Imamura F, Lemaitre RN, King IB, Song X, Lichtenstein AH, Matthan NR, et al.: Novel circulating fatty acid patterns and risk of cardiovascular disease: the Cardiovascular Health Study. Am J Clin Nutr 2012, 96:1252-61.
• [35]Mozaffarian D, Cao H, King IB, Lemaitre RN, Song X, Siscovick DS, et al.: Circulating palmitoleic acid and risk of metabolic abnormalities and new-onset diabetes. Am J Clin Nutr 2010, 92(6):1350-8.
• [36]Tynan GA, Hearnden CH, Oleszycka E, Lyons CL, Coutts G, O’Connell J, et al.: Endogenous Oils Derived From Human Adipocytes Are Potent Adjuvants That Promote IL-1α-Dependent Inflammation. Diabetes 2014, 63:2037-50.
• [37]Mironov VA, Gusev SA, Baradi AF: Mesothelial stomata overlying omental milky spots: Scanning electron microscopic study. Cell Tissue Res 1979, 201:327-30.
• [38]Schipper HS, Prakken B, Kalkhoven E, Boes M: Adipose tissue-resident immune cells: key players in immunometabolism. Trends Endocrinol Metab 2012, 23:407-15.
• [39]Micheel CM, Nass SJ, Omenn GS: Evolution of Translational Omics: Lessons Learned and the Path Forward. National Academies Press, Washington (DC); 2012.