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Maternal high-fat diet during suckling programs visceral adiposity and epigenetic regulation of adipose tissue stearoyl-CoA desaturase-1 in offspring

International Journal of Obesity (2019) | Download Citation

Abstract

Objective

The lactation-suckling period is critical for white adipose tissue (WAT) development. Early postnatal nutrition influences later obesity risk but underlying mechanisms remain elusive. Here, we tested whether altered postnatal nutrition specifically during suckling impacts epigenetic regulation of key metabolic genes in WAT and alter long-term adiposity set point.

Methods

We analyzed the effects of maternal high-fat (HF) feeding in rats exclusively during lactation-suckling on breast milk composition and its impact on male offspring visceral epidydimal (eWAT) and subcutaneous inguinal (iWAT) depots during suckling and in adulthood.

Results

Maternal HF feeding during lactation had no effect on mothers’ body weight (BW) or global breast milk composition, but induced qualitative changes in breast milk fatty acid (FA) composition (high n-6/n-3 polyunsaturated FA ratio and low medium-chain FA content). During suckling, HF neonates showed increased BW and mass of both eWAT and iWAT depot but only eWAT displayed an enhanced adipogenic transcriptional signature. In adulthood, HF offspring were predisposed to weight gain and showed increased hyperplastic growth only in eWAT. This specific eWAT expansion was associated with increased expression and activity of stearoyl-CoA desaturase-1 (SCD1), a key enzyme of FA metabolism. SCD1 converts saturated FAs, e.g. palmitate and stearate, to monounsaturated FAs, palmitoleate and oleate, which are the predominant substrates for triglyceride synthesis. Scd1 upregulation in eWAT was associated with reduced DNA methylation in Scd1 promoter surrounding a PPARγ-binding region. Conversely, changes in SCD1 levels and methylation were not observed in iWAT, coherent with a depot-specific programming.

Conclusions

Our data reveal that maternal HF feeding during suckling programs long-term eWAT expansion in part by SCD1 epigenetic reprogramming. This programming events occurred with drastic changes in breast milk FA composition, suggesting that dietary FAs are key metabolic programming factors in the early postnatal period.

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References

  1. 1.

    Zimmet P, Alberti KG, Kaufman F, Tajima N, Silink M, Arslanian S, et al. The metabolic syndrome in children and adolescents—an IDF consensus report. Pediatr Diabetes. 2007;8:299–306.

  2. 2.

    Lukaszewski MA, Eberle D, Vieau D, Breton C. Nutritional manipulations in the perinatal period program adipose tissue in offspring. Am J Physiol Endocrinol Metab. 2013;305:E1195–207.

  3. 3.

    Bouret S, Levin BE, Ozanne SE. Gene-environment interactions controlling energy and glucose homeostasis and the developmental origins of obesity. Physiol Rev. 2015;95:47–82.

  4. 4.

    Owen CG, Martin RM, Whincup PH, Smith GD, Cook DG. Effect of infant feeding on the risk of obesity across the life course: a quantitative review of published evidence. Pediatrics. 2005;115:1367–77.

  5. 5.

    Rudolph MC, Young BE, Lemas DJ, Palmer CE, Hernandez TL, Barbour LA, et al. Early infant adipose deposition is positively associated with the n-6 to n-3 fatty acid ratio in human milk independent of maternal BMI. Int J Obes. 2017;41:510–7.

  6. 6.

    Patel MS, Srinivasan M. Metabolic programming in the immediate postnatal life. Ann Nutr Metab. 2011;58(Suppl. 2):18–28.

  7. 7.

    Sun B, Purcell RH, Terrillion CE, Yan J, Moran TH, Tamashiro KL. Maternal high-fat diet during gestation or suckling differentially affects offspring leptin sensitivity and obesity. Diabetes. 2012;61:2833–41.

  8. 8.

    Desai M, Jellyman JK, Han G, Beall M, Lane RH, Ross MG. Maternal obesity and high-fat diet program offspring metabolic syndrome. Am J Obstet Gynecol. 2014;211:237 e1–237 e13.

  9. 9.

    Vogt MC, Paeger L, Hess S, Steculorum SM, Awazawa M, Hampel B, et al. Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high-fat feeding. Cell. 2014;156:495–509.

  10. 10.

    Carberry AE, Colditz PB, Lingwood BE. Body composition from birth to 4.5 months in infants born to non-obese women. Pediatr Res. 2010;68:84–8.

  11. 11.

    Birsoy K, Berry R, Wang T, Ceyhan O, Tavazoie S, Friedman JM, et al. Analysis of gene networks in white adipose tissue development reveals a role for ETS2 in adipogenesis. Development. 2011;138:4709–19.

  12. 12.

    Han J, Lee JE, Jin J, Lim JS, Oh N, Kim K, et al. The spatiotemporal development of adipose tissue. Development. 2011;138:5027–37.

  13. 13.

    Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med. 2013;19:1338–44.

  14. 14.

    Knittle JL, Timmers K, Ginsberg-Fellner F, Brown RE, Katz DP. The growth of adipose tissue in children and adolescents. Cross-sectional and longitudinal studies of adipose cell number and size. J Clin Invest. 1979;63:239–46.

  15. 15.

    Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, et al. Dynamics of fat cell turnover in humans. Nature. 2008;453:783–7.

  16. 16.

    Borengasser SJ, Zhong Y, Kang P, Lindsey F, Ronis MJ, Badger TM, et al. Maternal obesity enhances white adipose tissue differentiation and alters genome-scale DNA methylation in male rat offspring. Endocrinology. 2013;154:4113–25.

  17. 17.

    Liang X, Yang Q, Fu X, Rogers CJ, Wang B, Pan H, et al. Maternal obesity epigenetically alters visceral fat progenitor cell properties in male offspring mice. J Physiol. 2016;594:4453–66.

  18. 18.

    Lecoutre S, Oger F, Pourpe C, Butruille L, Marousez L, Dickes-Coopman A, et al. Maternal obesity programs increased leptin gene expression in rat male offspring via epigenetic modifications in a depot-specific manner. Mol Metab. 2017;6:922–30.

  19. 19.

    Lecoutre S, Pourpe C, Butruille L, Marousez L, Laborie C, Guinez C, et al. Reduced PPARgamma2 expression in adipose tissue of male rat offspring from obese dams is associated with epigenetic modifications. FASEB J. 2018;32:2768–78.

  20. 20.

    Dearden L, Bouret SG, Ozanne SE. Sex and gender differences in developmental programming of metabolism. Mol Metab. 2018;15:8–19.

  21. 21.

    Lecoutre S, Deracinois B, Laborie C, Eberle D, Guinez C, Panchenko PE, et al. Depot- and sex-specific effects of maternal obesity in offspring’s adipose tissue. J Endocrinol. 2016;230:39–53.

  22. 22.

    Gors S, Kucia M, Langhammer M, Junghans P, Metges CC. Technical note: Milk composition in mice—methodological aspects and effects of mouse strain and lactation day. J Dairy Sci. 2009;92:632–7.

  23. 23.

    Pedrono F, Boulier-Monthean N, Catheline D, Legrand P. Impact of a standard rodent chow diet on tissue n-6 fatty acids, delta9-desaturation index, and plasmalogen mass in rats fed for one year. Lipids. 2015;50:1069–82.

  24. 24.

    Jones BH, Maher MA, Banz WJ, Zemel MB, Whelan J, Smith PJ, et al. Adipose tissue stearoyl-CoA desaturase mRNA is increased by obesity and decreased by polyunsaturated fatty acids. Am J Physiol. 1996;271:E44–9.

  25. 25.

    Mutch DM. Identifying regulatory hubs in obesity with nutrigenomics. Curr Opin Endocrinol Diabetes. 2006;13:431–7.

  26. 26.

    Carobbio S, Rodriguez-Cuenca S, Vidal-Puig A. Origins of metabolic complications in obesity: ectopic fat accumulation. The importance of the qualitative aspect of lipotoxicity. Curr Opin Clin Nutr Metab Care. 2011;14:520–6.

  27. 27.

    Cedernaes J, Alsio J, Vastermark A, Riserus U, Schioth HB. Adipose tissue stearoyl-CoA desaturase 1 index is increased and linoleic acid is decreased in obesity-prone rats fed a high-fat diet. Lipids Health Dis. 2013;12:2.

  28. 28.

    Yew Tan C, Virtue S, Murfitt S, Roberts LD, Phua YH, Dale M, et al. Adipose tissue fatty acid chain length and mono-unsaturation increases with obesity and insulin resistance. Sci Rep. 2015;5:18366.

  29. 29.

    Man WC, Miyazaki M, Chu K, Ntambi J. Colocalization of SCD1 and DGAT2: implying preference for endogenous monounsaturated fatty acids in triglyceride synthesis. J Lipid Res. 2006;47:1928–39.

  30. 30.

    Mihara K. Structure and regulation of rat liver microsomal stearoyl-CoA desaturase gene. J Biochem. 1990;108:1022–9.

  31. 31.

    ALJohani AM, Syed DN, Ntambi JM. Insights into stearoyl-CoA desaturase-1 regulation of systemic metabolism. Trends Endocrinol Metab. 2017;28:831–42.

  32. 32.

    Ntambi JM. Regulation of stearoyl-CoA desaturase by polyunsaturated fatty acids and cholesterol. J Lipid Res. 1999;40:1549–58.

  33. 33.

    Soccio RE, Chen ER, Rajapurkar SR, Safabakhsh P, Marinis JM, Dispirito JR, et al. Genetic variation determines PPARgamma function and anti-diabetic drug response in vivo. Cell. 2015;162:33–44.

  34. 34.

    Nielsen R, Pedersen TA, Hagenbeek D, Moulos P, Siersbaek R, Megens E, et al. Genome-wide profiling of PPARgamma:RXR and RNA polymerase II occupancy reveals temporal activation of distinct metabolic pathways and changes in RXR dimer composition during adipogenesis. Genes Dev. 2008;22:2953–67.

  35. 35.

    Bray GA, Lee M, Bray TL. Weight gain of rats fed medium-chain triglycerides is less than rats fed long-chain triglycerides. Int J Obes. 1980;4:27–32.

  36. 36.

    Geliebter A, Torbay N, Bracco EF, Hashim SA, Van Itallie TB. Overfeeding with medium-chain triglyceride diet results in diminished deposition of fat. Am J Clin Nutr. 1983;37:1–4.

  37. 37.

    Muhlhausler BS, Ailhaud GP. Omega-6 polyunsaturated fatty acids and the early origins of obesity. Curr Opin Endocrinol Diabetes Obes. 2013;20:56–61.

  38. 38.

    Innis SM. Metabolic programming of long-term outcomes due to fatty acid nutrition in early life. Matern Child Nutr. 2011;7(Suppl. 2):112–23.

  39. 39.

    Cawthorn WP, Scheller EL, MacDougald OA. Adipose tissue stem cells meet preadipocyte commitment: going back to the future. J Lipid Res. 2012;53:227–46.

  40. 40.

    Jeffery E, Church CD, Holtrup B, Colman L, Rodeheffer MS. Rapid depot-specific activation of adipocyte precursor cells at the onset of obesity. Nat Cell Biol. 2015;17:376–85.

  41. 41.

    Shao M, Vishvanath L, Busbuso NC, Hepler C, Shan B, Sharma AX, et al. De novo adipocyte differentiation from Pdgfrbeta(+) preadipocytes protects against pathologic visceral adipose expansion in obesity. Nat Commun. 2018;9:890.

  42. 42.

    Carobbio S, Hagen RM, Lelliott CJ, Slawik M, Medina-Gomez G, Tan CY, et al. Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity. Diabetes. 2013;62:3697–708.

  43. 43.

    Kolak M, Yki-Jarvinen H, Kannisto K, Tiikkainen M, Hamsten A, Eriksson P, et al. Effects of chronic rosiglitazone therapy on gene expression in human adipose tissue in vivo in patients with type 2 diabetes. J Clin Endocrinol Metab. 2007;92:720–4.

  44. 44.

    Yao-Borengasser A, Rassouli N, Varma V, Bodles AM, Rasouli N, Unal R, et al. Stearoyl-coenzyme A desaturase 1 gene expression increases after pioglitazone treatment and is associated with peroxisomal proliferator-activated receptor-gamma responsiveness. J Clin Endocrinol Metab. 2008;93:4431–9.

  45. 45.

    Flowers MT, Ade L, Strable MS, Ntambi JM. Combined deletion of SCD1 from adipose tissue and liver does not protect mice from obesity. J Lipid Res. 2012;53:1646–53.

  46. 46.

    Ralston JC, Badoud F, Cattrysse B, McNicholas PD, Mutch DM. Inhibition of stearoyl-CoA desaturase-1 in differentiating 3T3-L1 preadipocytes upregulates elongase 6 and downregulates genes affecting triacylglycerol synthesis. Int J Obes. 2014;38:1449–56.

  47. 47.

    Ralston JC, Mutch DM. SCD1 inhibition during 3T3-L1 adipocyte differentiation remodels triacylglycerol, diacylglycerol and phospholipid fatty acid composition. Prostaglandins Leukot Essent Fat Acids. 2015;98:29–37.

  48. 48.

    Dragos SM, Bergeron KF, Desmarais F, Suitor K, Wright DC, Mounier C, et al. Reduced SCD1 activity alters markers of fatty acid reesterification, glyceroneogenesis, and lipolysis in murine white adipose tissue and 3T3-L1 adipocytes. Am J Physiol Cell Physiol. 2017;313:C295–304.

  49. 49.

    Cao H, Gerhold K, Mayers JR, Wiest MM, Watkins SM, Hotamisligil GS. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell. 2008;134:933–44.

  50. 50.

    Hyun CK, Kim ED, Flowers MT, Liu X, Kim E, Strable M, et al. Adipose-specific deletion of stearoyl-CoA desaturase 1 up-regulates the glucose transporter GLUT1 in adipose tissue. Biochem Biophys Res Commun. 2010;399:480–6.

  51. 51.

    Liang X, Yang Q, Zhang L, Maricelli JW, Rodgers BD, Zhu MJ, et al. Maternal high-fat diet during lactation impairs thermogenic function of brown adipose tissue in offspring mice. Sci Rep. 2016;6:34345.

  52. 52.

    Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P, et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 2009;41:178–86.

  53. 53.

    Rao X, Evans J, Chae H, Pilrose J, Kim S, Yan P, et al. CpG island shore methylation regulates caveolin-1 expression in breast cancer. Oncogene. 2013;32:4519–28.

  54. 54.

    Fradin D, Boelle PY, Belot MP, Lachaux F, Tost J, Besse C, et al. Genome-wide methylation analysis identifies specific epigenetic marks in severely obese children. Sci Rep. 2017;7:46311.

  55. 55.

    Breton CV, Marsit CJ, Faustman E, Nadeau K, Goodrich JM, Dolinoy DC, et al. Small-magnitude effect sizes in epigenetic end points are important in children’s environmental health studies: The Children’s Environmental Health and Disease Prevention Research Center’s Epigenetics Working Group. Environ Health Perspect. 2017;125:511–26.

  56. 56.

    Fujiki K, Shinoda A, Kano F, Sato R, Shirahige K, Murata M. PPARgamma-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine. Nat Commun. 2013;4:2262.

  57. 57.

    Yuan X, Tsujimoto K, Hashimoto K, Kawahori K, Hanzawa N, Hamaguchi M, et al. Epigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood. Nat Commun. 2018;9:636.

  58. 58.

    Verduci E, Banderali G, Barberi S, Radaelli G, Lops A, Betti F, et al. Epigenetic effects of human breast milk. Nutrients. 2014;6:1711–24.

  59. 59.

    Eriksen KG, Christensen SH, Lind MV, Michaelsen KF. Human milk composition and infant growth. Curr Opin Clin Nutr Metab Care. 2018;21:200–6.

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Acknowledgements

The authors thank Valérie Montel, Anne Dickes-Coopman, and Phexmar animal housing facility for excellent technical support, BICeL facility for microscopy, and Joel Haas for critical review of the manuscript. This study was supported by grants of the French Ministry of Higher Education and Research, of Lille University (BQR 2014) and from the French “Heart and Arteries” Foundation. Laura Butruille and Lucie Marousez were supported by grants from Metropole Européenne Lilloise (MEL) and Conseil Régional des Hauts-de-France.

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Author notes

  1. These authors contributed equally: Laura Butruille, Lucie Marousez

Affiliations

  1. Univ. Lille, EA4489, Équipe Malnutrition Maternelle et Programmation des Maladies Métaboliques, F-59000, Lille, France

    • Laura Butruille
    • , Lucie Marousez
    • , Charlène Pourpe
    • , Frédérik Oger
    • , Simon Lecoutre
    • , Céline Guinez
    • , Christine Laborie
    • , Philippe Deruelle
    • , Christophe Breton
    • , Jean Lesage
    •  & Delphine Eberlé
  2. Laboratoire de Biochimie et Nutrition Humaine INRA 1378, Agrocampus Ouest, 65 rue de Saint Brieuc, 35042, Rennes cedex, France

    • Daniel Catheline
    •  & Philippe Legrand
  3. Leibniz Institute for Farm Animal Biology (FBN), Institute of Nutritional Physiology, D-18196, Dummerstorf, Germany

    • Solvig Görs
    •  & Cornelia C. Metges
  4. Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000, Lille, France

    • Jérôme Eeckhoute

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The authors declare that they have no conflict of interest.

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Correspondence to Delphine Eberlé.

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DOI

https://doi.org/10.1038/s41366-018-0310-z