Download PDF
Exp Clin Endocrinol Diabetes 2021; 129(09): 674-682
DOI: 10.1055/a-1150-7446
Article

Epigenetic Downregulation of FASN in Visceral Adipose Tissue of Insulin Resistant Subjects

Helen Sievert
1   First Medical Department, University of Lübeck, Lübeck, Germany
,
Christin Krause
1   First Medical Department, University of Lübeck, Lübeck, Germany
,
Cathleen Geißler
1   First Medical Department, University of Lübeck, Lübeck, Germany
,
Martina Grohs
1   First Medical Department, University of Lübeck, Lübeck, Germany
,
Alexander T. El-Gammal
2   Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
Stefan Wolter
2   Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
Oliver Mann
2   Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
,
Hendrik Lehnert
1   First Medical Department, University of Lübeck, Lübeck, Germany
3   German Diabetes Center (DZD), München-Neuherberg, Germany
,
Henriette Kirchner
1   First Medical Department, University of Lübeck, Lübeck, Germany
3   German Diabetes Center (DZD), München-Neuherberg, Germany
› Author Affiliations Funding: This work was supported by funding from Deutsche Forschungsgemeinschaft (KI 1887/2–1 and GRK-1957).
› Further Information
Also available at
    Permissions and Reprints

Abstract

Objective The risk to develop type 2 diabetes increases with the amount of visceral adiposity presumably due to increased lipolysis and subsequent lipid accumulation in visceral organs. However, data describing the molecular regulation of these pathways in humans are rare. We tested if genes of the lipogenic and lipolytic pathways are associated with glucose intolerance independently of obesity in visceral adipose tissue (VAT) of obese subjects. Moreover, we studied DNA methylation of FASN (fatty acid synthase), that catalyses the synthesis of long-chain fatty acids, in VAT of the same subjects and whether it is associated with metabolic traits.

Subjects and methods Visceral adipose tissue biopsies and blood samples were taken from 93 severely obese subjects undergoing bariatric surgery. Subjects were grouped in low HbA1c (L-HbA1c, HbA1c<6.5 %) and high HbA1c (H-HbA1c, HbA1c≥6.5 %) groups and expression of genes from the lipogenic and lipolytic pathways was analysed by TaqMan qPCR. DNA methylation of FASN was quantified by bisulfite-pyrosequencing.

Results FASN expression was downregulated in visceral fat from subjects with high HbA1c (p = 0.00009). Expression of other lipogenetic (SCD, ELOVL6) or lipolytic genes (ADRB3, PNPLA2) and FABP4 was not changed. DNA methylation of FASN was increased at a regulatory ChoRE recognition site in the H-HbA1c-subgroup and correlated negatively with FASN mRNA (r = − 0.302, p = 0.0034) and positively with HbA1c (r = 0.296, p = 0.0040) and blood glucose (r = 0.363, p = 0.0005).

Conclusions Epigenetic downregulation of FASN in visceral adipose tissue of obese subjects might contribute to limited de novo lipogenesis of important insulin sensitizing fatty acids and could thereby contribute to glucose intolerance and the development of type 2 diabetes independently of obesity.

Key words

type 2 diabetes - obesity - DNA methylation - ChREBP1 - HbA1c - visceral adipose tissue

Supplementary Material



Publication History

Received: 26 August 2019
Received: 12 March 2020

Accepted: 30 March 2020

Article published online:
20 May 2020

© 2019. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Huang-Doran I, Sleigh A, Rochford JJ. et al. Lipodystrophy: Metabolic insights from a rare disorder. J Endocrinol 2010; 207: 245-255 DOI: 10.1677/JOE-10-0272
    CrossrefPubMedGoogle Scholar
  • 2 Abbasi F, Brown BW, Lamendola C. et al. Relationship between obesity, insulin resistance, and coronary heart disease risk. J Am Coll Cardiol 2002; 40: 937-943. Doi 10.1016/S0735-1097(02)02051-X
    CrossrefPubMedGoogle Scholar
  • 3 Kirchhoff K, Kantartzis K, Machann J. et al. Impact of different fat depots on insulin sensitivity: Predominant role of liver fat. J Diabetes Sci Technol 2007; 1: 753-759 DOI: 10.1177/193229680700100521
    CrossrefPubMedGoogle Scholar
  • 4 Scherer PE. The many secret lives of adipocytes: Implications for diabetes. Diabetologia 2019; 62: 223-232 DOI: 10.1007/s00125-018-4777-x
    CrossrefPubMedGoogle Scholar
  • 5 Tchernof A, Despres JP. Pathophysiology of human visceral obesity: An update. Physiol Rev 2013; 93: 359-404 DOI: 10.1152/physrev.00033.2011
    CrossrefPubMedGoogle Scholar
  • 6 Ibrahim MM. Subcutaneous and visceral adipose tissue: Structural and functional differences. Obes Rev 2010; 11: 11-18 DOI: 10.1111/j.1467-789X.2009.00623.x
    CrossrefPubMedGoogle Scholar
  • 7 Arner P. Differences in lipolysis between human subcutaneous and omental adipose tissues. Ann Med 1995; 27: 435-438 DOI: 10.3109/07853899709002451
    CrossrefPubMedGoogle Scholar
  • 8 Arner P, Langin D. Lipolysis in lipid turnover, cancer cachexia, and obesity-induced insulin resistance. Trends Endocrinol Metab 2014; 25: 255-262 DOI: 10.1016/j.tem.2014.03.002
    CrossrefPubMedGoogle Scholar
  • 9 Karpe F, Dickmann JR, Frayn KN. Fatty acids, obesity, and insulin resistance: Time for a reevaluation. Diabetes 2011; 60: 2441-2449 DOI: 10.2337/db11-0425
    CrossrefPubMedGoogle Scholar
  • 10 Eissing L, Scherer T, Todter K. et al. De novo lipogenesis in human fat and liver is linked to ChREBP-beta and metabolic health. Nat Commun 2013; 4: 1528 DOI: 10.1038/ncomms2537
    CrossrefPubMedGoogle Scholar
  • 11 Thomou T, Mori MA, Dreyfuss JM. et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 2017; 542: 450-455 DOI: 10.1038/nature21365
    CrossrefPubMedGoogle Scholar
  • 12 Arner P, Sinha I, Thorell A. et al. The epigenetic signature of subcutaneous fat cells is linked to altered expression of genes implicated in lipid metabolism in obese women. Clin Epigenetics 2015; 7: 93 DOI: 10.1186/s13148-015-0126-9
    CrossrefPubMedGoogle Scholar
  • 13 Keller M, Hopp L, Liu X. et al. Genome-wide DNA promoter methylation and transcriptome analysis in human adipose tissue unravels novel candidate genes for obesity. Mol Metab 2017; 6: 86-100 DOI: 10.1016/j.molmet.2016.11.003
    CrossrefPubMedGoogle Scholar
  • 14 Nilsson E, Jansson PA, Perfilyev A. et al. Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes. Diabetes 2014; 63: 2962-2976 DOI: 10.2337/db13-1459
    CrossrefPubMedGoogle Scholar
  • 15 Kersten S. Mechanisms of nutritional and hormonal regulation of lipogenesis. EMBO Rep 2001; 2: 282-286 DOI: 10.1093/embo-reports/kve071
    CrossrefPubMedGoogle Scholar
  • 16 Matsuzaka T, Shimano H. Elovl6: A new player in fatty acid metabolism and insulin sensitivity. J Mol Med (Berl) 2009; 87: 379-384 DOI: 10.1007/s00109-009-0449-0
    CrossrefPubMedGoogle Scholar
  • 17 Strable MS, Ntambi JM. Genetic control of de novo lipogenesis: Role in diet-induced obesity. Crit Rev Biochem Mol Biol 2010; 45: 199-214 DOI: 10.3109/10409231003667500
    CrossrefPubMedGoogle Scholar
  • 18 Arner P, Langin D. Lipolysis in lipid turnover, cancer cachexia, and obesity-induced insulin resistance. Trends in Endocrinology and Metabolism: TEM 2014; 25: 255-262 DOI: 10.1016/j.tem.2014.03.002
    CrossrefPubMedGoogle Scholar
  • 19 Duncan RE, Ahmadian M, Jaworski K. et al. Regulation of lipolysis in adipocytes. Annual Review of Nutrition 2007; 27: 79-101 DOI: 10.1146/annurev.nutr.27.061406.093734
    CrossrefPubMedGoogle Scholar
  • 20 Lass A, Zimmermann R, Oberer M. et al. Lipolysis - a highly regulated multi-enzyme complex mediates the catabolism of cellular fat stores. Progress in lipid Research 2011; 50: 14-27 DOI: 10.1016/j.plipres.2010.10.004
    CrossrefPubMedGoogle Scholar
  • 21 Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Research 2001; 29: e45 DOI: 10.1093/nar/29.9.e45
    CrossrefPubMedGoogle Scholar
  • 22 Eissing L, Scherer T, Todter K. et al. De novo lipogenesis in human fat and liver is linked to ChREBP-beta and metabolic health. Nature communications 2013; 4: 1528 DOI: 10.1038/ncomms2537
    CrossrefPubMedGoogle Scholar
  • 23 Ma L, Robinson LN, Towle HC. ChREBP*Mlx is the principal mediator of glucose-induced gene expression in the liver. The Journal of Biological Chemistry 2006; 281: 28721-28730 DOI: 10.1074/jbc.M601576200
    CrossrefPubMedGoogle Scholar
  • 24 Poungvarin N, Chang B, Imamura M. et al. Genome-wide analysis of ChREBP binding sites on male mouse liver and white adipose chromatin. Endocrinology 2015; 156: 1982-1994 DOI: 10.1210/en.2014-1666
    CrossrefPubMedGoogle Scholar
  • 25 Colella AD, Chegenii N, Tea MN. et al. Comparison of Stain-Free gels with traditional immunoblot loading control methodology. Anal Biochem 2012; 430: 108-110 DOI: 10.1016/j.ab.2012.08.015
    CrossrefPubMedGoogle Scholar
  • 26 Guenard F, Tchernof A, Deshaies Y. et al. Differential methylation in visceral adipose tissue of obese men discordant for metabolic disturbances. Physiol Genomics 2014; 46: 216-222 DOI: 10.1152/physiolgenomics.00160.2013
    CrossrefPubMedGoogle Scholar
  • 27 Hotamisligil GS, Johnson RS, Distel RJ. et al. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 1996; 274: 1377-1379 DOI: 10.1126/science.274.5291.1377
    CrossrefPubMedGoogle Scholar
  • 28 Ma L, Robinson LN, Towle HC. ChREBP*Mlx is the principal mediator of glucose-induced gene expression in the liver. J Biol Chem 2006; 281: 28721-28730 DOI: 10.1074/jbc.M601576200
    CrossrefPubMedGoogle Scholar
  • 29 Kim JB, Spotts GD, Halvorsen YD. et al. Dual DNA binding specificity of ADD1/SREBP1 controlled by a single amino acid in the basic helix-loop-helix domain. Mol Cell Biol 1995; 15: 2582-2588 DOI: 10.1128/mcb.15.5.2582
    CrossrefPubMedGoogle Scholar
  • 30 Ishii S, Iizuka K, Miller BC. et al. Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription. Proc Natl Acad Sci USA 2004; 101: 15597-15602 DOI: 10.1073/pnas.0405238101
    CrossrefPubMedGoogle Scholar
  • 31 Horton JD, Shah NA, Warrington JA. et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci USA 2003; 100: 12027-12032 DOI: 10.1073/pnas.1534923100
    CrossrefPubMedGoogle Scholar
  • 32 Shih HM, Liu Z, Towle HC. Two CACGTG motifs with proper spacing dictate the carbohydrate regulation of hepatic gene transcription. The Journal of biological chemistry 1995; 270: 21991-21997 DOI: 10.1074/jbc.270.37.21991
    CrossrefPubMedGoogle Scholar
  • 33 Reed BD, Charos AE, Szekely AM. et al. Genome-wide occupancy of SREBP1 and its partners NFY and SP1 reveals novel functional roles and combinatorial regulation of distinct classes of genes. PLoS genetics 2008; 4: e1000133 DOI: 10.1371/journal.pgen.1000133
    CrossrefPubMedGoogle Scholar
  • 34 Davegardh C, Garcia-Calzon S, Bacos K. et al. DNA methylation in the pathogenesis of type 2 diabetes in humans. Mol Metab 2018; 14: 12-25 DOI: 10.1016/j.molmet.2018.01.022
    CrossrefPubMedGoogle Scholar
  • 35 Kirchner H, Osler ME, Krook A. et al. Epigenetic flexibility in metabolic regulation: disease cause and prevention?. Trends in cell biology 2013; 23: 203-209 DOI: 10.1016/j.tcb.2012.11.008
    CrossrefPubMedGoogle Scholar
  • 36 Wakil SJ. Fatty-Acid Synthase, a Proficient Multifunctional Enzyme. Biochemistry-Us 1989; 28: 4523-4530 DOI: Doi 10.1021/Bi00437a001
    CrossrefPubMedGoogle Scholar
  • 37 Mayas MD, Ortega FJ, Macias-Gonzalez M. et al. Inverse relation between FASN expression in human adipose tissue and the insulin resistance level. Nutr Metab 2010; 7 DOI: Artn 310.1186/1743-7075-7-3
    PubMedGoogle Scholar
  • 38 Ortega FJ, Mayas D, Moreno-Navarrete JM. et al. The gene expression of the main lipogenic enzymes is downregulated in visceral adipose tissue of obese subjects. Obesity (Silver Spring) 2010; 18: 13-20 DOI: 10.1038/oby.2009.202
    CrossrefPubMedGoogle Scholar
  • 39 Berndt J, Kovacs P, Ruschke K. et al. Fatty acid synthase gene expression in human adipose tissue: Association with obesity and type 2 diabetes. Diabetologia 2007; 50: 1472-1480 DOI: 10.1007/s00125-007-0689-x
    CrossrefPubMedGoogle Scholar
  • 40 Coupe C, Perdereau D, Ferre P. et al. Lipogenic enzyme activities and mRNA in rat adipose tissue at weaning. Am J Physiol 1990; 258: E126-E133 DOI: 10.1152/ajpendo.1990.258.1.E126
    PubMedGoogle Scholar
  • 41 Nuotio-Antar AM, Poungvarin N, Li M. et al. FABP4-Cre mediated expression of constitutively active ChREBP protects against obesity, fatty liver, and insulin resistance. Endocrinology 2015; 156: 4020-4032 DOI: 10.1210/en.2015-1210
    CrossrefPubMedGoogle Scholar
  • 42 Kirchner H, Sinha I, Gao H. et al. Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients. Mol Metab 2016; 5: 171-183 DOI: 10.1016/j.molmet.2015.12.004
    CrossrefPubMedGoogle Scholar
  • 43 Herman MA, Peroni OD, Villoria J. et al. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 2012; 484: 333-338 DOI: 10.1038/nature10986
    CrossrefPubMedGoogle Scholar
  • 44 Cao H, Gerhold K, Mayers JR. et al. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 2008; 134: 933-944 DOI: 10.1016/j.cell.2008.07.048
    CrossrefPubMedGoogle Scholar
  • 45 Yore MM, Syed I, Moraes-Vieira PM. et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 2014; 159: 318-332 DOI: 10.1016/j.cell.2014.09.035
    CrossrefPubMedGoogle Scholar
  • 46 Yilmaz M, Claiborn KC, Hotamisligil GS. De novo lipogenesis products and endogenous lipokines. Diabetes 2016; 65: 1800-1807 DOI: 10.2337/db16-0251
    CrossrefPubMedGoogle Scholar