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Father’s obesity programs the adipose tissue in the offspring via the local renin–angiotensin system and MAPKs pathways, especially in adult male mice

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Abstract

Purpose

Studies demonstrated the influence of mother’s obesity on offspring. However, the father is also related to programming the future generation. The study aimed to evaluate the effects of father’s obesity upon white adipose tissue (WAT) remodeling, resulting in activation of signaling pathways and inflammation in male and female offspring.

Methods

Male C57BL/6 mice received control diet (lean father group; 17% energy from lipids) or high-fat diet (obese father group; 49% energy from lipids) for 8 weeks before mating. The mothers received control diet throughout the experiment. Mice were mated: lean mother and lean father, and lean mother and obese father. Offspring received control diet from weaning until 3 months of age when they were studied.

Results

In the offspring, father’s obesity led to decreased QUICKI with impairment of the insulin signaling pathway in both sexes. In line with these findings, in white adipose tissue, male offspring demonstrated hypertrophied adipocytes, enhanced proinflammatory cytokines, overactivation of components of the local renin–angiotensin system (RAS) and extracellular signal-regulated kinase 1/2 (ERK1/2), and inhibition of peroxisome proliferator-activated receptors (alpha and gamma).

Conclusions

We observed that father’s obesity influences the offspring in adult life, with an impairment in insulin homeostasis, adipocyte remodeling, and adipose tissue overexpression of IL-6 and TNF-alpha in male offspring. The activation of local RAS and ERK1/2, a concomitant PPAR diminishing, and impairment in phosphorylation of AKT and IRS-1 could explain at least in part the findings regardless of the increase in body mass in the offspring.

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Abbreviations

AMPK:

AMP-activated protein kinase

AT1r:

Ang-II type 1 receptor

ACE:

Angiotensin-converting enzyme

Ang-II:

Angiotensin-II

JNK:

c-Jun N-terminal kinase

ERK1/2:

Extracellular signal-regulated kinase 1/2

NFκB:

Factor nuclear kappa B

IRS-1:

Insulin receptor substrate 1

IL:

Interleukin-6

MAPKs:

Mitogen-activated protein kinases

PPAR:

Peroxisome proliferator-activated receptor

PKB or AKT:

Protein kinase B

RAS:

Renin–angiotensin system

TBP:

TATA box-binding protein

TNF:

Tumor necrosis factor-alpha

WAT:

White adipose tissue

References

  1. Flegal KM, Carroll MD, Kit BK, Ogden CL (2012) Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA 307(5):491–497. doi:10.1001/jama.2012.39

    Article  PubMed  Google Scholar 

  2. Bringhenti I, Moraes-Teixeira JA, Cunha MR, Ornellas F, Mandarim-de-Lacerda CA, Aguila MB (2013) Maternal obesity during the preconception and early life periods alters pancreatic development in early and adult life in male mouse offspring. PLoS One 8(1):e55711. doi:10.1371/journal.pone.0055711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bringhenti I, Ornellas F, Mandarim-de-Lacerda CA, Aguila MB (2016) The insulin-signaling pathway of the pancreatic islet is impaired in adult mice offspring of mothers fed a high-fat diet. Nutrition 32(10):1138–1143. doi:10.1016/j.nut.2016.03.001

    Article  CAS  PubMed  Google Scholar 

  4. Gregorio BM, Souza-Mello V, Mandarim-de-Lacerda CA, Aguila MB (2013) Maternal high-fat diet is associated with altered pancreatic remodelling in mice offspring. Eur J Nutr 52(2):759–769. doi:10.1007/s00394-012-0382-9

    Article  CAS  PubMed  Google Scholar 

  5. Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ (2010) Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467(7318):963–966. doi:10.1038/nature09491

    Article  CAS  PubMed  Google Scholar 

  6. Ng SF, Lin RC, Maloney CA, Youngson NA, Owens JA, Morris MJ (2014) Paternal high-fat diet consumption induces common changes in the transcriptomes of retroperitoneal adipose and pancreatic islet tissues in female rat offspring. FASEB J 28(4):1830–1841. doi:10.1096/fj.13-244046

    Article  CAS  PubMed  Google Scholar 

  7. Liu HQ, Qiu Y, Mu Y, Zhang XJ, Liu L, Hou XH, Zhang L, Xu XN, Ji AL, Cao R, Yang RH, Wang F (2013) A high ratio of dietary n-3/n-6 polyunsaturated fatty acids improves obesity-linked inflammation and insulin resistance through suppressing activation of TLR4 in SD rats. Nutr Res 33(10):849–858. doi:10.1016/j.nutres.2013.07.004

    Article  CAS  PubMed  Google Scholar 

  8. Siriwardhana N, Kalupahana NS, Cekanova M, LeMieux M, Greer B, Moustaid-Moussa N (2013) Modulation of adipose tissue inflammation by bioactive food compounds. J Nutr Biochem 24(4):613–623. doi:10.1016/j.jnutbio.2012.12.013

    Article  CAS  PubMed  Google Scholar 

  9. Wang C, Chang Q, Sun X, Qian X, Liu P, Pei H, Guo X, Liu W (2015) Angiotensin II induces an increase in matrix metalloproteinase 2 expression in aortic smooth muscle cells of ascending thoracic aortic aneurysms through JNK, ERK1/2, and p38 MAPK activation. J Cardiovasc Pharmacol 66(3):285–293. doi:10.1097/FJC.0000276

    Article  CAS  PubMed  Google Scholar 

  10. Cropley JE, Eaton SA, Aiken A, Young PE, Giannoulatou E, Ho JW, Buckland ME, Keam SP, Hutvagner G, Humphreys DT, Langley KG, Henstridge DC, Martin DI, Febbraio MA, Suter CM (2016) Male-lineage transmission of an acquired metabolic phenotype induced by grand-paternal obesity. Mol Metab 5(8):699–708. doi:10.1016/j.molmet.2016.06.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Slyvka Y, Zhang Y, Nowak FV (2015) Epigenetic effects of paternal diet on offspring: emphasis on obesity. Endocrine 48(1):36–46. doi:10.1007/s12020-014-0328-5

    Article  CAS  PubMed  Google Scholar 

  12. Reeves PG, Nielsen FH, Fahey GC Jr (1993) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 123(11):1939–1951

    Article  CAS  PubMed  Google Scholar 

  13. Cruz-Orive LM, Weibel ER (1990) Recent stereological methods for cell biology: a brief survey. Am J Physiol 258(4 Pt 1):L148–156

    CAS  PubMed  Google Scholar 

  14. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ (2000) Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 85(7):2402–2410. doi:10.1210/jcem.85.7.6661

    Article  CAS  Google Scholar 

  15. Mandarim-de-Lacerda CA (2003) Stereological tools in biomedical research. An Acad Bras Cienc 75(4):469–486. doi:10.1590/S0001-37652003000400006

    Article  PubMed  Google Scholar 

  16. Bargut TC, Mandarim-de-Lacerda CA, Aguila MB (2015) A high-fish-oil diet prevents adiposity and modulates white adipose tissue inflammation pathways in mice. J Nutr Biochem 26(9):960–969. doi:10.1016/j.jnutbio.2015.04.002

    Article  CAS  PubMed  Google Scholar 

  17. McPherson NO, Lane M, Sandeman L, Owens JA, Fullston T (2017) An exercise-only intervention in obese fathers restores glucose and insulin regulation in conjunction with the rescue of pancreatic islet cell morphology and MicroRNA expression in male offspring. Nutrients. doi:10.3390/nu9020122

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ornellas F, Souza-Mello V, Mandarim-de-Lacerda CA, Aguila MB (2015) Programming of obesity and comorbidities in the progeny: lessons from a model of diet-induced obese parents. PLoS One 10(4):e0124737. doi:10.1371/journal.pone.0124737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ornellas F, Souza-Mello V, Mandarim-de-Lacerda CA, Aguila MB (2016) Combined parental obesity augments single-parent obesity effects on hypothalamus inflammation, leptin signaling (JAK/STAT), hyperphagia, and obesity in the adult mice offspring. Physiol Behav 153:47–55. doi:10.1016/j.physbeh.2015.10.019

    Article  CAS  PubMed  Google Scholar 

  20. Chowdhury SS, Lecomte V, Erlich JH, Maloney CA, Morris MJ (2016) Paternal high fat diet in rats leads to renal accumulation of lipid and tubular changes in adult offspring. Nutrients. doi:10.3390/nu8090521

    Article  PubMed  PubMed Central  Google Scholar 

  21. Fullston T, Ohlsson Teague EM, Palmer NO, DeBlasio MJ, Mitchell M, Corbett M, Print CG, Owens JA, Lane M (2013) Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content. FASEB J 27(10):4226–4243. doi:10.1096/fj.12-224048

    Article  CAS  PubMed  Google Scholar 

  22. Fullston T, McPherson NO, Owens JA, Kang WX, Sandeman LY, Lane M (2015) Paternal obesity induces metabolic and sperm disturbances in male offspring that are exacerbated by their exposure to an “obesogenic” diet. Physiol Rep. doi:10.14814/phy2.12336

    Article  PubMed  PubMed Central  Google Scholar 

  23. Heard E, Martienssen RA (2014) Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157(1):95–109. doi:10.1016/j.cell.2014.02.045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Binder NK, Beard SA, Kaitu’u-Lino TJ, Tong S, Hannan NJ, Gardner DK (2015) Paternal obesity in a rodent model affects placental gene expression in a sex-specific manner. Reproduction 149(5):435–444. doi:10.1530/REP-14-0676

    Article  CAS  PubMed  Google Scholar 

  25. Guerrero-Bosagna C, Skinner MK (2014) Environmentally induced epigenetic transgenerational inheritance of male infertility. Curr Opin Genet Dev 26:79–88. doi:10.1016/j.gde.2014.06.005

    Article  CAS  PubMed  Google Scholar 

  26. Casas E, Vavouri T (2014) Sperm epigenomics: challenges and opportunities. Front Genet 5:330. doi:10.3389/fgene.2014.00330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Botton J, Heude B, Maccario J, Borys JM, Lommez A, Ducimetiere P, Charles MA, group Fs (2010) Parental body size and early weight and height growth velocities in their offspring. Early Hum Dev 86(7):445–450. doi:10.1016/j.earlhumdev.2010.06.001

    Article  PubMed  Google Scholar 

  28. Figueras M, Olivan M, Busquets S, Lopez-Soriano FJ, Argiles JM (2011) Effects of eicosapentaenoic acid (EPA) treatment on insulin sensitivity in an animal model of diabetes: improvement of the inflammatory status. Obesity (Silver Spring) 19(2):362–369. doi:10.1038/oby.2010.194

    Article  CAS  Google Scholar 

  29. Angin Y, Beauloye C, Horman S, Bertrand L (2016) Regulation of carbohydrate metabolism, lipid metabolism, and protein metabolism by AMPK. EXS 107:23–43. doi:10.1007/978-3-319-43589-3_2

    Article  CAS  PubMed  Google Scholar 

  30. Ornellas F, Mello VS, Mandarim-de-Lacerda CA, Aguila MB (2013) Sexual dimorphism in fat distribution and metabolic profile in mice offspring from diet-induced obese mothers. Life Sci 93(12–14):454–463. doi:10.1016/j.lfs.2013.08.005

    Article  CAS  PubMed  Google Scholar 

  31. Morita S, Nakabayashi K, Kawai T, Hayashi K, Horii T, Kimura M, Kamei Y, Ogawa Y, Hata K, Hatada I (2016) Gene expression profiling of white adipose tissue reveals paternal transmission of proneness to obesity. Sci Rep 6:21693. doi:10.1038/srep21693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Masuyama H, Mitsui T, Eguchi T, Tamada S, Hiramatsu Y (2016) The effects of paternal high-fat diet exposure on offspring metabolism with epigenetic changes in the mouse adiponectin and leptin gene promoters. Am J Physiol Endocrinol Metab 311(1):E236–245. doi:10.1152/ajpendo.00095.2016

    Article  PubMed  Google Scholar 

  33. Jacobs MD, Harrison SC (1998) Structure of an IkappaBalpha/NF-kappaB complex. Cell 95(6):749–758

    Article  CAS  PubMed  Google Scholar 

  34. Calder PC (2012) Mechanisms of action of (n-3) fatty acids. J Nutr 142(3):592S–599S. doi:10.3945/jn.111.155259

    Article  CAS  PubMed  Google Scholar 

  35. Janke J, Engeli S, Gorzelniak K, Luft FC, Sharma AM (2002) Mature adipocytes inhibit in vitro differentiation of human preadipocytes via angiotensin type 1 receptors. Diabetes 51(6):1699–1707

    Article  CAS  PubMed  Google Scholar 

  36. Engeli S, Negrel R, Sharma AM (2000) Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension 35(6):1270–1277

    Article  CAS  PubMed  Google Scholar 

  37. Kalupahana NS, Moustaid-Moussa N (2012) The adipose tissue renin-angiotensin system and metabolic disorders: a review of molecular mechanisms. Crit Rev Biochem Mol Biol 47(4):379–390. doi:10.3109/10409238.2012.694843

    Article  CAS  PubMed  Google Scholar 

  38. Kim S, Soltani-Bejnood M, Quignard-Boulange A, Massiera F, Teboul M, Ailhaud G, Kim JH, Moustaid-Moussa N, Voy BH (2006) The adipose renin-angiotensin system modulates systemic markers of insulin sensitivity and activates the intrarenal renin-angiotensin system. J Biomed Biotechnol 5:27012. doi:10.1155/JBB/2006/27012

    Article  CAS  Google Scholar 

  39. Frigolet ME, Torres N, Tovar AR (2013) The renin-angiotensin system in adipose tissue and its metabolic consequences during obesity. J Nutr Biochem 24(12):2003–2015. doi:10.1016/j.jnutbio.2013.07.002

    Article  CAS  PubMed  Google Scholar 

  40. Tanti JF, Gremeaux T, van Obberghen E, Le Marchand-Brustel Y (1994) Serine/threonine phosphorylation of insulin receptor substrate 1 modulates insulin receptor signaling. J Biol Chem 269(8):6051–6057

    CAS  PubMed  Google Scholar 

  41. Santos SH, Fernandes LR, Mario EG, Ferreira AV, Porto LC, Alvarez-Leite JI, Botion LM, Bader M, Alenina N, Santos RA (2008) Mas deficiency in FVB/N mice produces marked changes in lipid and glycemic metabolism. Diabetes 57(2):340–347. doi:10.2337/db07-0953

    Article  CAS  PubMed  Google Scholar 

  42. Tsuchiya K, Yoshimoto T, Hirono Y, Tateno T, Sugiyama T, Hirata Y (2006) Angiotensin II induces monocyte chemoattractant protein-1 expression via a nuclear factor-kappaB-dependent pathway in rat preadipocytes. Am J Physiol Endocrinol Metab 291(4):E771–778. doi:10.1152/ajpendo.00560.2005

    Article  CAS  PubMed  Google Scholar 

  43. Ramalingam L, Menikdiwela K, LeMieux M, Dufour JM, Kaur G, Kalupahana N, Moustaid-Moussa N (2016) The renin angiotensin system, oxidative stress and mitochondrial function in obesity and insulin resistance. Biochim Biophys Acta. doi:10.1016/j.bbadis.2016.07.019

    Article  Google Scholar 

  44. Tham DM, Martin-McNulty B, Wang YX, Wilson DW, Vergona R, Sullivan ME, Dole W, Rutledge JC (2002) Angiotensin II is associated with activation of NF-kappaB-mediated genes and downregulation of PPARs. Physiol Genom 11(1):21–30. doi:10.1152/physiolgenomics.00062.2002

    Article  CAS  Google Scholar 

  45. Tapia G, Valenzuela R, Espinosa A, Romanque P, Dossi C, Gonzalez-Manan D, Videla LA, D’Espessailles A (2014) N-3 long-chain PUFA supplementation prevents high fat diet induced mouse liver steatosis and inflammation in relation to PPAR-alpha upregulation and NF-kappaB DNA binding abrogation. Mol Nutr Food Res 58(6):1333–1341. doi:10.1002/mnfr.201300458

    Article  CAS  PubMed  Google Scholar 

  46. Kintscher U, Law RE (2005) PPARgamma-mediated insulin sensitization: the importance of fat versus muscle. Am J Physiol Endocrinol Metab 288(2):E287–291. doi:10.1152/ajpendo.00440.2004

    Article  CAS  PubMed  Google Scholar 

  47. Medina-Gomez G, Gray S, Vidal-Puig A (2007) Adipogenesis and lipotoxicity: role of peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgammacoactivator-1 (PGC1). Public Health Nutr 10(10A):1132–1137. doi:10.1017/S1368980007000614

    Article  PubMed  Google Scholar 

  48. Meng Y, Chen C, Tian C, Du J, Li HH (2015) Angiotensin II-induced Egr-1 expression is suppressed by peroxisome proliferator-activated receptor-gamma ligand 15d-PGJ(2) in macrophages. Cell Physiol Biochem 35(2):689–698. doi:10.1159/000369729

    Article  CAS  PubMed  Google Scholar 

  49. Sugawara A, Uruno A, Kudo M, Matsuda K, Yang CW, Ito S (2010) Effects of PPARgamma on hypertension, atherosclerosis, and chronic kidney disease. Endocr J 57(10):847–852

    Article  CAS  PubMed  Google Scholar 

  50. Montecucco F, Liberale L, Bonaventura A, Vecchie A, Dallegri F, Carbone F (2017) The role of inflammation in cardiovascular outcome. Curr Atheroscler Rep 19(3):11. doi:10.1007/s11883-017-0646-1

    Article  CAS  PubMed  Google Scholar 

  51. Looijenga LH, Gillis AJ, Verkerk AJ, van Putten WL, Oosterhuis JW (1999) Heterogeneous X inactivation in trophoblastic cells of human full-term female placentas. Am J Hum Genet 64(5):1445–1452. doi:10.1086/302382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Clifton VL (2010) Review: sex and the human placenta: mediating differential strategies of fetal growth and survival. Placenta 31(Suppl):S33–39. doi:10.1016/j.placenta.2009.11.010

    Article  CAS  PubMed  Google Scholar 

  53. Binder NK, Hannan NJ, Gardner DK (2012) Paternal diet-induced obesity retards early mouse embryo development, mitochondrial activity and pregnancy health. PLoS One 7(12):e52304. doi:10.1371/journal.pone.0052304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Link JC, Hasin-Brumshtein Y, Cantor RM, Chen X, Arnold AP, Lusis AJ, Reue K (2017) Diet, gonadal sex, and sex chromosome complement influence white adipose tissue miRNA expression. BMC Genom 18(1):89. doi:10.1186/s12864-017-3484-1

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank Michele Soares and Aline Penna de Carvalho for technical assistance.

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Authors and Affiliations

  1. Universidade do Estado do Rio de Janeiro, Centro Biomédico, Instituto de Biologia, Laboratório de Morfometria, Metabolismo e Doença Cardiovascular, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil

    Fernanda Ornellas, Isabele Bringhenti, Brenda Akemi N. F. Mattos, Carlos Alberto Mandarim-de-Lacerda & Marcia Barbosa Aguila

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  1. Fernanda Ornellas
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  2. Isabele Bringhenti
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  3. Brenda Akemi N. F. Mattos
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  4. Carlos Alberto Mandarim-de-Lacerda
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  5. Marcia Barbosa Aguila
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Contributions

Conception/design of the work: FO, MBA; Data collection: FO.

IB, BM; Data analysis and interpretation: FO, IB, CAML, MBA; Drafting the article: FO, IB.

MBA; Critical revision of the article: CAML, MBA; Final approval of the version to be published: CAML, MBA.

Corresponding author

Correspondence to Carlos Alberto Mandarim-de-Lacerda.

Ethics declarations

Experimental protocol was approved by the Ethics Committee of the State University of Rio de Janeiro (Protocol Number CEUA 070/2012).

Conflict of interest

The authors disclose no conflict of interest in the study.

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Ornellas, F., Bringhenti, I., Mattos, B.A.N.F. et al. Father’s obesity programs the adipose tissue in the offspring via the local renin–angiotensin system and MAPKs pathways, especially in adult male mice. Eur J Nutr 57, 1901–1912 (2018). https://doi.org/10.1007/s00394-017-1473-4

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