FABP4 dynamics in obesity: discrepancies in adipose tissue and liver expression regarding circulating plasma levels

María Isabel Queipo-Ortuño, Xavier Escoté, Victoria Ceperuelo-Mallafré, Lourdes Garrido-Sanchez, Merce Miranda, Mercedes Clemente-Postigo, Rafael Pérez-Pérez, Belen Peral, Fernando Cardona, Jose Manuel Fernández-Real, Francisco J Tinahones, Joan Vendrell, María Isabel Queipo-Ortuño, Xavier Escoté, Victoria Ceperuelo-Mallafré, Lourdes Garrido-Sanchez, Merce Miranda, Mercedes Clemente-Postigo, Rafael Pérez-Pérez, Belen Peral, Fernando Cardona, Jose Manuel Fernández-Real, Francisco J Tinahones, Joan Vendrell

Abstract

Background: FABP4 is predominantly expressed in adipose tissue, and its circulating levels are linked with obesity and a poor atherogenic profile.

Objective: In patients with a wide BMI range, we analyze FABP4 expression in adipose and hepatic tissues in the settings of obesity and insulin resistance. Associations between FABP4 expression in adipose tissue and the FABP4 plasma level as well as the main adipogenic and lipolytic genes expressed in adipose tissue were also analyzed.

Methods: The expression of several lipogenic, lipolytic, PPAR family and FABP family genes was analyzed by real time PCR. FABP4 protein expression in total adipose tissues and its fractions were determined by western blot.

Results: In obesity FABP4 expression was down-regulated (at both mRNA and protein levels), with its levels mainly predicted by ATGL and inversely by the HOMA-IR index. The BMI appeared as the only determinant of the FABP4 variation in both adipose tissue depots. FABP4 plasma levels showed a significant progressive increase according to BMI but no association was detected between FABP4 circulating levels and SAT or VAT FABP4 gene expression. The gene expression of FABP1, FABP4 and FABP5 in hepatic tissue was significantly higher in tissue from the obese IR patients compared to the non-IR group.

Conclusion: The inverse pattern in FABP4 expression between adipose and hepatic tissue observed in morbid obese patients, regarding the IR context, suggests that both tissues may act in a balanced manner. These differences may help us to understand the discrepancies between circulating plasma levels and adipose tissue expression in obesity.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. FABP4 expression is higher in…
Figure 1. FABP4 expression is higher in isolated adipocytes (ADI) than in the stromovascular fraction (SVF).
(A) FABP4 mRNA expression levels in ADI and SVF from n = 15 subjects with paired adipose biopsies (ADI vs. SVF, *P = 0.001). Data are expressed as median and IQR. (B) FABP4 protein levels in total VAT, and in ADI and SVF fractions, from n = 4 subjects. Data are expressed as mean and SD. (ADI vs. SVF, ¶P<0.05) (C) Representative blot of FABP4 protein in total VAT and SAT, and in ADI and SVF fractions. (D) Immunofluorescence detection of FABP4 (red) and CD68 (green) in VAT. The counterstaining of nuclei (DAPI) is shown in blue. Images are representative of VAT collected from five subjects. (E) Immnunohistochemical detection of FABP4 (brown, right panel) and CD68 (macrophage-specific antigen, middle panel) and negative control (left panel) in VAT. Images are representative of VAT sections collected from five subjects. A: Adipocyte; M: Macrophage. Arrow-heads indicate the specific signal.
Figure 2. FABP4 expression in adipose and…
Figure 2. FABP4 expression in adipose and liver tissues from mice.
Fasting mRNA expression of FABP4 visceral adipose tissue in ob/ob (n = 16) (grey bar) and WT (n = 16) (black bar) mouse. Adipose tissue expression level of the gene was normalized using β-actin. The results are given as the mean ± SD. *indicates significant differences between the means of the two groups (P<0.05). (B) Fasting mRNA expression levels of hepatic FABP1 and FABP4 in ob/ob (n = 16) (grey bar) and WT (n = 16) (black bar) mouse. Hepatic tissue expression levels for each gene were normalized using GADPH. The results are given as the mean±SD. *indicates significant differences between the means of the two groups (P<0.05).

References

    1. Coe NR, Bernlohr DA (1998) Physiological properties and functions of intracellular fatty acid-binding proteins. Biochim Biophys Acta 1391: 287–306.
    1. Hertzel AV, Bernlohr DA (2000) The mammalian fatty acid-binding protein multigene family: molecular and genetic insights into function. Trends Endocrinol Metab 11: 175–180.
    1. Maeda K, Cao H, Kono K, Gorgun CZ, Furuhashi M, et al. (2005) Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell Metab 1: 107–119.
    1. Xu A, Tso AW, Cheung BM, Wang Y, Wat NM, et al. (2007) Circulating adipocyte-fatty acid binding protein levels predict the development of the metabolic syndrome: a 5-year prospective study. Circulation 115: 1537–1543.
    1. Xu A, Wang Y, Yu SJ, Stejskal D, Tam S, et al. (2006) Adypocite fatty acid-binding protein is a plasma biomarker associated with obesity and Metabolic Syndrome. Clin Chem 52: 405–413.
    1. Makowski L, Hotamisligil GS (2004) Fatty acid binding-proteins-the evolutionary crossroads of inflammatory and metabolic responses. J Nutr 134: 2464S–2468S.
    1. Hotamisligil GS, Johnson RJ, Distel RJ, Ellis R, Papaioannou VE, et al. (1996) Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 274: 1377–1379.
    1. Boord JB, Maeda K, Makowski L, Babaev VR, Fazio S, et al. (2002) Adipocyte fatty acid binding protein, aP2, alters late atherosclerotic lesion formation in severe hypercholesterolemia. Arterioscler Thromb Vas Biol 22: 1686–1691.
    1. Makowski L, Boord JB, Maeda K, Babaev VR, Uysal KT, et al. (2001) Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat Med 7: 699–705.
    1. Cabre A, Lazaro I, Cofan M, Jarauta E, Plana N, et al. (2009) FABP4 plasma levels are increased in familial combined hyperlipidemia. J Lipid Res 51(5): 1173–8.
    1. Cabre A, Lazaro I, Girona J, Manzanares JM, Marimón F, et al. (2007) Fatty acid binding protein 4 is increased in metabolic syndrome and with thiazolidinedione treatment in diabetic patients. Atherosclerosis 195: e150–8.
    1. Cabre A, Lazaro I, Girona J, Manzanares JM, Marimón F, et al. (2008) Plasma fatty acid-binding protein 4 increases with renal dysfunction in type 2 diabetic patients without microalbuminuria. Clin Chem 54: 181–7.
    1. Cabre A, Lazaro I, Girona J, Manzanares JM, Marimón F, et al. (2008) Plasma fatty acid binding protein 4 is associated with atherogenic dyslipidemia in diabetes. J Lipid Res 49: 1746–51.
    1. Coll B, Cabre A, Alonso-Villaverde C, Lazaro I, Aragonés G, et al. (2008) The fatty acid binding protein-4 (FABP4) is a strong biomarker of metabolic syndrome and lipodystrophy in HIV-infected patients. Atherosclerosis 199: 147–53.
    1. Bao Y, Lu Z, Zhou M, Li H, Wang Y, et al. (2010) Serum levels of adipocyte fatty acid-binding protein are associated with the severity of coronary artery disease in Chinese women. PLoS One 6(4): e19115.
    1. Koh JH, Shin YG, Nam SM, Lee MY, Chung CH, et al. (2009) Serum adipocyte fatty acid-binding protein levels are associated with nonalcoholic fatty liver disease in type 2 diabetic patients. Diabetes Care 32: 147–15.
    1. Tso A, Xu AW, Sham P, Wat NM, Wang Y, et al. (2007) Serum adipocyte fatty acid-binding protein as a new biomarker predicting the development of type 2 diabetes. Diabetes Care 30: 2667–2672.
    1. Stejskal D, Karpisek M (2006) Adypocite fatty acid binding protein in Caucasian population: a new marker of metabolic syndrome?. Eur J Clin Invest 36: 621–625.
    1. Furuhashi M, Hotamisligil GS (2008) Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 7: 489–503.
    1. Després JP, Lemieux I (2006) Abdominal obesity and metabolic syndrome. Nature 444: 881–887.
    1. Klöting N, Fasshauer M, Dietrich A, Kovacs P, Schön MR, et al. (2010) Insulin sensitive obesity. Am J Physiol Endocrinol Metab 299: 506–515.
    1. Miranda M, Escoté X, Ceperuelo-Mallafré V, Alcaide MJ, Simón I, et al. (2010) Paired subcutaneous and visceral adipose tissue aquaporin-7 expression in human obesity and type 2 diabetes: differences and similarities between depots. J Clin Endocrinol Metab 95: 3470–3479.
    1. Drolet R, Richard C, Sniderman AD, Mailloux J, Fortier M, et al. (2008) Hypertrophy and hyperplasia of abdominal adipose tissues in women. Int J Obes (Lond) 32(2): 283–291.
    1. Fisher RM, Eriksson P, Hoffstedt J, Hotamisligil GS, Thörne A, et al. (2001) Fatty acid binding protein expression in different adipose tissue depots from lean and obese individuals. Diabetologia 44(10): 1268–1273.
    1. Poulain-Godefroy O, Lecoeur C, Pattou F, Frühbeck G, Froguel P (2008) Inflammation is associated with a decrease of lipogenic factors in omental fat in women. Am J Physiol Regul Integr Comp Physiol 295(1): R1–7.
    1. Clemente-Postigo M, Queipo-Ortuño MI, Fernandez-Garcia D, Gomez-Huelgas R, Tinahones FJ, et al. (2011) Adipose tissue gene expression of factors related to lipid processing in obesity. PLoS One 6(9): e24783.
    1. Shearer J, Fueger PT, Bracy DP, Wasserman DH, Rottman JN (2005) Partial gene deletion of heart-type fatty acid-binding protein limits the severity of dietary-induced insulin resistance. Diabetes 54: 3133–3139.
    1. World Health Organization (2000) Obesity: Preventing and Managing the Global Epidemic. In WHO (eds). WHO Technical Report Series 894, Geneva, Switzerland.
    1. Garcia-Fuentes E, Murri M, Garrido-Sanchez L, Garcia-Serrano S, García-Almeida JM, et al. (2009) PPARγ expression after a high-fat meal is associated with plasma superoxide dismutase activity in morbidly obese persons. Obesity 18: 952–958.
    1. Ceperuelo-Mallafré V, Näf S, Escoté X, Caubet E, Gomez JM, et al. (2009) Circulating and adipose tissue gene expression of zinc-alpha2-glycoprotein in obesity: its relationship with adipokine and lipolytic gene markers in subcutaneous and visceral fat. J Clin Endocrinol Metab 94: 5062–5069.
    1. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, et al. (2005) Sources of fatty acids stored in liver and secreted via lipoproteins in patients with non alcoholic fatty liver disease. J Clin Invest 115: 1343–1351.
    1. Bagheri R, Lehrke M, Kapoor S, Wolfe M, Terembula K, et al. (2007) Plasma Levels of Fatty Acid Binding Proteins 4 and 5 are Markers of Adiposity and the Metabolic Syndrome but are not Independent Predictors of Subclinical Atherosclerosis in Type 2 Diabetes. Circulation 116: 270.
    1. Tinahones FJ, Garrido-Sanchez L, Miranda M, García-Almeida JM, Macias-Gonzalez M, et al. (2010) Obesity and Insulin Resistance-Related Changes in the Expression of Lipogenic and Lipolytic Genes in Morbidly Obese Subjects. Obes Surg 20: 1559–1567.
    1. Shankar SS, Steinberg HO (2005) FFAs: do they play a role in vascular disease in the insulin resistance syndrome?. Curr Diab Rep 5: 30–35.
    1. Pirro M, Mauriege P, Tchernof A, Cantin B, Dagenais GR, et al. (2002) Plasma free fatty acid levels and the risk of ischemic heart disease in men: prospective results from the Quebec Cardiovascular Study. Atherosclerosis 160: 377–384.
    1. Roden M (2007) Blocking fatty acids’ mystery tour: a therapy for metabolic syndrome?. Cell Metab 6: 89–91.
    1. Terra X, Quintero Y, Auguet T, Porras JA, Hernández M, et al. (2011) FABP4 is associated with inflammatory markers and metabolic syndrome in morbidly obese women. Eur J Endocrinol 164: 539–547.
    1. Moller DE, Kaufman KD (2005) Metabolic syndrome: a clinical and molecular perspective. Annu Rev Med 56: 45–62.
    1. Zeyda M, Stulnig TM (2009) Obesity, inflammation, and insulinresistance-a mini-review. Gerontology 55: 379–386.
    1. Slawik M, Vidal-Puig AJ (2007) Adipose tissue expandability and the metabolic syndrome. Genes Nutr 2: 41–45.
    1. Gaemers IC, Stallen JM, Kunne C, Wallner C, van Werven J, et al. (2011) Lipotoxicity and steatohepatitis in an over fed mouse model for non-alcoholic fatty liver disease. Biochim Biophys Acta 1812: 447–458.
    1. Klimcáková E, Roussel B, Márquez-Quiñones A, Kovácová Z, Kováciková M, et al. (2011) Worsening of obesity and metabolic status yields similar molecular adaptations in human subcutaneous and visceral adipose tissue: decreased metabolism and increased immune response. J Clin Endocrinol Metab 96: 73–82.
    1. Yang R, Castriota G, Chen Y, Cleary MA, Ellsworth K, et al. (2011) RNAi-mediated germline knockdown of FABP4 increases body weight but does not improve the deranged nutrient metabolism of diet-induced obese mice. Int J Obes 35: 217–225.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe