Article | Published:

Pediatrics

Mitochondrial inefficiency in infants born to overweight African-American mothers

International Journal of Obesityvolume 42pages13061316 (2018) | Download Citation

Abstract

Background

Currently 20–35% of pregnant women are obese, posing a major health risk for mother and fetus. It is postulated that an abnormal maternal-fetal nutritional environment leads to adverse metabolic programming, resulting in altered substrate metabolism in the offspring and predisposing to risks of obesity and diabetes later in life. Data indicate that oocytes from overweight animals have abnormal mitochondria. We hypothesized that maternal obesity is associated with altered mitochondrial function in healthy neonatal offspring.

Methods

Overweight and obese (body mass index, (BMI) ≥ 25 kg/m2, n = 14) and lean (BMI < 25 kg/m2, n = 8), African-American pregnant women carrying male fetuses were recruited from the Barnes Jewish Hospital obstetric clinic. Maternal and infant data were extracted from medical records. Infants underwent body composition testing in the first days of life. Circumcision skin was collected for isolation of fibroblasts. Fibroblast cells were evaluated for mitochondrial function, metabolic gene expression, nutrient uptake, and oxidative stress.

Results

Skin fibroblasts of infants born to overweight mothers had significantly higher mitochondrial respiration without a concurrent increase in ATP production, indicating mitochondrial inefficiency. These fibroblasts had higher levels of reactive oxygen species and evidence of oxidative stress. Evaluation of gene expression in offspring fibroblasts revealed altered expression of multiple genes involved in fatty acid and glucose metabolism and mitochondrial respiration in infants of overweight mothers.

Conclusions

This study demonstrates altered mitochondrial function and oxidative stress in skin fibroblasts of infants born to overweight mothers. Future studies are needed to determine the long-term impact of this finding on the metabolic health of these children.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Seidell JC. Obesity, insulin resistance and diabetes--a worldwide epidemic. Br J Nutr. 2000;83:S5–8. Suppl 1

  2. 2.

    Vahratian A. Prevalence of overweight and obesity among women of childbearing age: results from the 2002 National Survey of Family Growth. Matern Child Health J. 2009;13:268–73.

  3. 3.

    Branum AM, Kirmeyer SE, Gregory EC. Prepregnancy body mass index by maternal characteristics and state: data from the birth certificate, 2014. Natl Vital Stat Rep. 2016;65:1–11.

  4. 4.

    Chen A, Feresu SA, Fernandez C, Rogan WJ. Maternal obesity and the risk of infant death in the United States. Epidemiology. 2009;20:74–81.

  5. 5.

    Metwally M, Ong KJ, Ledger WL, Li TC. Does high body mass index increase the risk of miscarriage after spontaneous and assisted conception? A meta-analysis of the evidence. Fertil Steril. 2008;90:714–26.

  6. 6.

    Stothard KJ, Tennant PW, Bell R, Rankin J. Maternal overweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. JAMA. 2009;301:636–50.

  7. 7.

    Oken E. Maternal and child obesity: the causal link. Obstet Gynecol Clin North Am. 2009;36:361–77.

  8. 8.

    Perng W, Gillman MW, Mantzoros CS, Oken E. A prospective study of maternal prenatal weight and offspring cardiometabolic health in midchildhood. Ann Epidemiol. 2014;24:793–800 e1.

  9. 9.

    Catalano PM, Presley L, Minium J, Hauguel-de Mouzon S. Fetuses of obese mothers develop insulin resistance in utero. Diabetes Care. 2009;32:1076–80.

  10. 10.

    Modi N, Murgasova D, Ruager-Martin R, Thomas EL, Hyde MJ, Gale C, et al. The influence of maternal body mass index on infant adiposity and hepatic lipid content. Pediatr Res. 2011;70:287–91.

  11. 11.

    Barker DJ. The origins of the developmental origins theory. J Intern Med. 2007;261:412–7.

  12. 12.

    Barker DJ. Fetal origins of coronary heart disease. BMJ. 1995;311:171–4.

  13. 13.

    Samuelsson AM, Matthews PA, Argenton M, Christie MR, McConnell JM, Jansen EH, et al. Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertension. 2008;51:383–92.

  14. 14.

    Shankar K, Harrell A, Liu X, Gilchrist JM, Ronis MJ, Badger TM. Maternal obesity at conception programs obesity in the offspring. Am J Physiol Regul Integr Comp Physiol. 2008;294:R528–38.

  15. 15.

    Zambrano E, Nathanielsz PW. Mechanisms by which maternal obesity programs offspring for obesity: evidence from animal studies. Nutr Rev. 2013;71:S42–54. Suppl 1

  16. 16.

    Muhlhausler BS. Programming of the appetite-regulating neural network: a link between maternal overnutrition and the programming of obesity? J Neuroendocrinol. 2007;19:67–72.

  17. 17.

    Guan H, Arany E, van Beek JP, Chamson-Reig A, Thyssen S, Hill DJ, et al. Adipose tissue gene expression profiling reveals distinct molecular pathways that define visceral adiposity in offspring of maternal protein-restricted rats. Am J Physiol Endocrinol Metab. 2005;288:E663–73.

  18. 18.

    Desai M, Gayle D, Babu J, Ross MG. Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition. Am J Physiol Regul Integr Comp Physiol. 2005;288:R91–6.

  19. 19.

    Wang Q, Frolova AI, Purcell S, Adastra K, Schoeller E, Chi MM, et al. Mitochondrial dysfunction and apoptosis in cumulus cells of type I diabetic mice. PLoS ONE. 2010;5:e15901.

  20. 20.

    Luzzo KM, Wang Q, Purcell SH, Chi M, Jimenez PT, Grindler N, et al. High fat diet induced developmental defects in the mouse: oocyte meiotic aneuploidy and fetal growth retardation/brain defects. PLoS ONE. 2012;7:e49217.

  21. 21.

    Wu LL, Dunning KR, Yang X, Russell DL, Lane M, Norman RJ, et al. High-fat diet causes lipotoxicity responses in cumulus-oocyte complexes and decreased fertilization rates. Endocrinology. 2010;151:5438–45.

  22. 22.

    Saben JL, Boudoures AL, Asghar Z, Thompson A, Drury A, Zhang W, et al. Maternal metabolic syndrome programs mitochondrial dysfunction via germline changes across three generations. Cell Rep. 2016;16:1–8.

  23. 23.

    Igosheva N, Abramov AY, Poston L, Eckert JJ, Fleming TP, Duchen MR, et al. Maternal diet-induced obesity alters mitochondrial activity and redox status in mouse oocytes and zygotes. PLoS ONE. 2010;5:e10074.

  24. 24.

    Gemma C, Sookoian S, Alvarinas J, Garcia SI, Quintana L, Kanevsky D, et al. Mitochondrial DNA depletion in small- and large-for-gestational-age newborns. Obesity. 2006;14:2193–9.

  25. 25.

    Lopez LB, Calvo EB, Poy MS, del Valle Balmaceda Y, Camera K. Changes in skinfolds and mid-upper arm circumference during pregnancy in Argentine women. Matern Child Nutr. 2011;7:253–62.

  26. 26.

    Thame M, Trotman H, Osmond C, Fletcher H, Antoine M. Body composition in pregnancies of adolescents and mature women and the relationship to birth anthropometry. Eur J Clin Nutr. 2007;61:47–53.

  27. 27.

    Brand MD, Nicholls DG. Assessing mitochondrial dysfunction in cells. Biochem J. 2011;435:297–312.

  28. 28.

    Brookheart RT, Swearingen AR, Collins CA, Cline LM, Duncan JG. High-sucrose-induced maternal obesity disrupts ovarian function and decreases fertility in Drosophila melanogaster. Biochim Biophys Acta. 2017;1863:1255–63.

  29. 29.

    Ruiz R, Jideonwo V, Ahn M, Surendran S, Tagliabracci VS, Hou Y, et al. Sterol regulatory element-binding protein-1 (SREBP-1) is required to regulate glycogen synthesis and gluconeogenic gene expression in mouse liver. J Biol Chem. 2014;289:5510–7.

  30. 30.

    Duncan JG, Fong JL, Medeiros DM, Finck BN, Kelly DP. Insulin-resistant heart exhibits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-alpha/PGC-1alpha gene regulatory pathway. Circulation. 2007;115:909–17.

  31. 31.

    Brand MD, Affourtit C, Esteves TC, Green K, Lambert AJ, Miwa S, et al. Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med. 2004;37:755–67.

  32. 32.

    Ricquier D, Bouillaud F. Mitochondrial uncoupling proteins: from mitochondria to the regulation of energy balance. J Physiol. 2000;529:3–10. Pt 1

  33. 33.

    Arsenijevic D, Onuma H, Pecqueur C, Raimbault S, Manning BS, Miroux B, et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet. 2000;26:435–9.

  34. 34.

    Pheiffer C, Jacobs C, Patel O, Ghoor S, Muller C, Louw J. Expression of UCP2 in Wistar rats varies according to age and the severity of obesity. J Physiol Biochem. 2016;72:25–32.

  35. 35.

    Matsuda M, Shimomura I. Increased oxidative stress in obesity: implications for metabolic syndrome, diabetes, hypertension, dyslipidemia, atherosclerosis, and cancer. Obes Res Clin Pract. 2013;7:e330–41.

  36. 36.

    Le Lay S, Simard G, Martinez MC, Andriantsitohaina R. Oxidative stress and metabolic pathologies: from an adipocentric point of view. Oxid Med Cell Longev. 2014;2014:908539.

  37. 37.

    Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S, Stuart JA, et al. Superoxide activates mitochondrial uncoupling proteins. Nature. 2002;415:96–9.

  38. 38.

    Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000;408:239–47.

  39. 39.

    Lenaz G. Role of mitochondria in oxidative stress and ageing. Biochim Biophys Acta. 1998;1366:53–67.

  40. 40.

    Indo HP, Davidson M, Yen HC, Suenaga S, Tomita K, Nishii T, et al. Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage. Mitochondrion. 2007;7:106–18.

  41. 41.

    Majima HJ, Oberley TD, Furukawa K, Mattson MP, Yen HC, Szweda LI, et al. Prevention of mitochondrial injury by manganese superoxide dismutase reveals a primary mechanism for alkaline-induced cell death. J Biol Chem. 1998;273:8217–24.

  42. 42.

    Costa SM, Isganaitis E, Matthews TJ, Hughes K, Daher G, Dreyfuss JM, et al. Maternal obesity programs mitochondrial and lipid metabolism gene expression in infant umbilical vein endothelial cells. Int J Obes. 2016;40:1627–34.

  43. 43.

    Long NM, Rule DC, Zhu MJ, Nathanielsz PW, Ford SP. Maternal obesity upregulates fatty acid and glucose transporters and increases expression of enzymes mediating fatty acid biosynthesis in fetal adipose tissue depots. J Anim Sci. 2012;90:2201–10.

  44. 44.

    Trovato FM, Catalano D, Musumeci G, Trovato GM. 4Ps medicine of the fatty liver: the research model of predictive, preventive, personalized and participatory medicine-recommendations for facing obesity, fatty liver and fibrosis epidemics. EPMA J. 2014;5(1):21.

  45. 45.

    Prodanovic R, Koricanac G, Vujanac I, Djordjevic A, Pantelic M, Romic S, et al. Obesity-driven prepartal hepatic lipid accumulation in dairy cows is associated with increased CD36 and SREBP-1 expression. Res Vet Sci. 2016;107:16–9.

  46. 46.

    Pedersen O, Kahn CR, Kahn BB. Divergent regulation of the Glut 1 and Glut 4 glucose transporters in isolated adipocytes from Zucker rats. J Clin Invest. 1992;89:1964–73.

  47. 47.

    Takamura T, Misu H, Matsuzawa-Nagata N, Sakurai M, Ota T, Shimizu A, et al. Obesity upregulates genes involved in oxidative phosphorylation in livers of diabetic patients. Obesity. 2008;16:2601–9.

  48. 48.

    Tsintzas K, Norton L, Chokkalingam K, Nizamani N, Cooper S, Stephens F, et al. Independent and combined effects of acute physiological hyperglycaemia and hyperinsulinaemia on metabolic gene expression in human skeletal muscle. Clin Sci. 2013;124:675–84.

  49. 49.

    Coletta DK, Balas B, Chavez AO, Baig M, Abdul-Ghani M, Kashyap SR, et al. Effect of acute physiological hyperinsulinemia on gene expression in human skeletal muscle in vivo. Am J Physiol Endocrinol Metab. 2008;294:E910–7.

  50. 50.

    Samson R, Qi A, Jaiswal A, Le Jemtel TH, Oparil S. Obesity-associated hypertension: the upcoming phenotype in African-American women. Curr Hypertens Rep. 2017;19:41.

  51. 51.

    Fowler BA. Obesity in African-American women--the time bomb is ticking: an urgent call for change. J Natl Black Nurses Assoc. 2015;26:42–50.

  52. 52.

    Nwobu CO, Johnson CC. Targeting obesity to reduce the risk for type 2 diabetes and other co-morbidities in African American youth: a review of the literature and recommendations for prevention. Diab Vasc Dis Res. 2007;4:311–9.

  53. 53.

    Rodenburg RJ. Biochemical diagnosis of mitochondrial disorders. J Inherit Metab Dis. 2011;34:283–92.

Download references

Acknowledgements

This project was supported by the NIH/National Center for Advancing Translational Sciences (NCATS) grant UL1 TR000448. We thank the Women’s and Infant’s Health Consortium for assistance with cord blood collection and Lana Mehanovic for help with statistical analyses. LIFE-Moms is supported by the NIH through the NIDDK (U01 DK094418, U01 DK094463, U01 DK094416, 5U01 DK094466 (RCU)), the NHLBI (U01 HL114344, U01 HL114377), the NICHD (U01 HD072834), the NCCIH, the NIH Office of Research in Women’s Health (ORWH), the Office of Behavioral and Social Science Research (OBSSR), the Indian Health Service, and the Intramural Research Program of the NIDDK. We thank the LIFE-Moms consortium members for their contributions to the development and oversight of the common measures and procedures shared across trials.

Author information

Affiliations

  1. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA

    • Manjusha Abraham
    • , Christina A. Collins
    • , Scott Flewelling
    • , Maraya Camazine
    •  & Jennifer G. Duncan
  2. Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, USA

    • Alison Cahill
  3. Department of Physical Therapy, Washington University School of Medicine, St. Louis, MO, USA

    • W. Todd Cade

Authors

  1. Search for Manjusha Abraham in:

  2. Search for Christina A. Collins in:

  3. Search for Scott Flewelling in:

  4. Search for Maraya Camazine in:

  5. Search for Alison Cahill in:

  6. Search for W. Todd Cade in:

  7. Search for Jennifer G. Duncan in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Jennifer G. Duncan.

Electronic supplementary material

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/s41366-018-0051-z