Obesity is predominant in women of reproductive age. Roux-en-Y gastric bypass (RYGB) is the most common bariatric procedure that is performed in obese women for weight loss and metabolic improvement. However, some studies suggest that this procedure negatively affects offspring. Herein, using Western diet (WD)-obese female rats, we investigated the effects of maternal RYGB on postnatal body development, glucose tolerance, insulin secretion and action in their adult male F1 offspring.
Female Wistar rats consumed a Western diet (WD) for 18 weeks, before being submitted to RYGB (WD-RYGB) or SHAM (WD-SHAM) operations. After 5 weeks, WD-RYGB and WD-SHAM females were mated with control male breeders, and the F1 offspring were identified as: WD-RYGB-F1 and WD-SHAM-F1.
The male F1 offspring of WD-RYGB dams exhibited decreased BW, but enhanced total nasoanal length gain. At 120 days of age, WD-RYGB-F1 rats displayed normal fasting glycemia and glucose tolerance but demonstrated reduced insulinemia and higher glucose disappearance after insulin stimulus. In addition, these rodents presented insulin resistance in the gastrocnemius muscle and retroperitoneal fat, as judged by lower Akt phosphorylation after insulin administration, but an increase in this protein in the liver. Finally, the islets from WD-RYGB-F1 rats secreted less insulin in response to glucose and displayed increased β-cell area and mass.
RYGB in WD dams negatively affected their F1 offspring, leading to catch-up growth, insulin resistance in skeletal muscle and white fat, and β-cell dysfunction. Therefore, our data are the first to demonstrate that the RYGB in female rats may aggravate the metabolic imprinting induced by maternal WD consumption, in their male F1 descendants. However, since we only used male F1 rats, further studies are necessary to demonstrate if such effect may also occur in female F1 offspring from dams that underwent RYGB operation.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Collaborators GBDO, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, Marczak L, Mokdad AH, Moradi-Lakeh M, Naghavi M, Salama JS, Vos T, Abate KH, Abbafati C, Ahmed MB, Al-Aly Z, Alkerwi A, Al-Raddadi R, Amare AT, Amberbir A, Amegah AK, Amini E, Amrock SM, Anjana RM, Arnlov J, Asayesh H, Banerjee A, Barac A, Baye E, Bennett DA, Beyene AS, Biadgilign S, Biryukov S, Bjertness E, Boneya DJ, Campos-Nonato I, Carrero JJ, Cecilio P, Cercy K, Ciobanu LG, Cornaby L, Damtew SA, Dandona L, Dandona R, Dharmaratne SD, Duncan BB, Eshrati B, Esteghamati A, Feigin VL, Fernandes JC, Furst T, Gebrehiwot TT, Gold A, Gona PN, Goto A, Habtewold TD, Hadush KT, Hafezi-Nejad N, Hay SI, Horino M, Islami F, Kamal R, Kasaeian A, Katikireddi SV, Kengne AP, Kesavachandran CN, Khader YS, Khang YH, Khubchandani J, Kim D, Kim YJ, Kinfu Y, Kosen S, Ku T, Defo BK, Kumar GA, Larson HJ, Leinsalu M, Liang X, Lim SS, Liu P, Lopez AD, Lozano R, Majeed A, Malekzadeh R, Malta DC, Mazidi M, McAlinden C, McGarvey ST, Mengistu DT, Mensah GA, Mensink GBM, Mezgebe HB, Mirrakhimov EM, Mueller UO, Noubiap JJ, Obermeyer CM, Ogbo FA, Owolabi MO, Patton GC, Pourmalek F, Qorbani M, Rafay A, Rai RK, Ranabhat CL, Reinig N, Safiri S, Salomon JA, Sanabria JR, Santos IS, Sartorius B, Sawhney M, Schmidhuber J, Schutte AE, Schmidt MI, Sepanlou SG, Shamsizadeh M, Sheikhbahaei S, Shin MJ, Shiri R, Shiue I, Roba HS, Silva DAS, Silverberg JI, Singh JA, Stranges S, Swaminathan S, Tabares-Seisdedos R, Tadese F, Tedla BA, Tegegne BS, Terkawi AS, Thakur JS, Tonelli M, Topor-Madry R, Tyrovolas S, Ukwaja KN, Uthman OA, Vaezghasemi M, Vasankari T, Vlassov VV, Vollset SE, Weiderpass E, Werdecker A, Wesana J, Westerman R, Yano Y, Yonemoto N, Yonga G, Zaidi Z, Zenebe ZM, Zipkin B, Murray CJL (2017) Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med 377(1):13–27. https://doi.org/10.1056/NEJMoa1614362
Jacobsen BK, Knutsen SF, Oda K, Fraser GE (2012) Obesity at age 20 and the risk of miscarriages, irregular periods and reported problems of becoming pregnant: the Adventist Health Study-2. Eur J Epidemiol 27(12):923–931. https://doi.org/10.1007/s10654-012-9749-8
Poston L, Caleyachetty R, Cnattingius S, Corvalan C, Uauy R, Herring S, Gillman MW (2016) Preconceptional and maternal obesity: epidemiology and health consequences. Lancet Diabetes Endocrinol 4(12):1025–1036. https://doi.org/10.1016/S2213-8587(16)30217-0
Mitchell A, Fantasia HC (2016) Understanding the effect of obesity on fertility among reproductive-age women. Nurs Women’s Health 20(4):368–376. https://doi.org/10.1016/j.nwh.2016.07.001
Bautista-Castano I, Henriquez-Sanchez P, Aleman-Perez N, Garcia-Salvador JJ, Gonzalez-Quesada A, Garcia-Hernandez JA, Serra-Majem L (2013) Maternal obesity in early pregnancy and risk of adverse outcomes. PLoS One 8(11):e80410. https://doi.org/10.1371/journal.pone.0080410
Sinha R, Fisch G, Teague B, Tamborlane WV, Banyas B, Allen K, Savoye M, Rieger V, Taksali S, Barbetta G, Sherwin RS, Caprio S (2002) Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med 346(11):802–810. https://doi.org/10.1056/NEJMoa012578
Juonala M, Magnussen CG, Berenson GS, Venn A, Burns TL, Sabin MA, Srinivasan SR, Daniels SR, Davis PH, Chen W, Sun C, Cheung M, Viikari JS, Dwyer T, Raitakari OT (2011) Childhood adiposity, adult adiposity, and cardiovascular risk factors. N Engl J Med 365(20):1876–1885. https://doi.org/10.1056/NEJMoa1010112
Catalano PM, Shankar K (2017) Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child. BMJ 356:j1. https://doi.org/10.1136/bmj.j1
Sharma R, Biedenharn KR, Fedor JM, Agarwal A (2013) Lifestyle factors and reproductive health: taking control of your fertility. Reprod Biol Endocrinol 11:66. https://doi.org/10.1186/1477-7827-11-66
Andreassen MS, Ferraz LF, Jesus NR, Piano A, Azevedo CH, Perez AIC (2012) Evaluation of the fetal maternal binomial after bariatric surgery. BEPA Boletim Epidemiológico Paulista (Online) 9:21–29
Edison E, Whyte M, van Vlymen J, Jones S, Gatenby P, de Lusignan S, Shawe J (2016) Bariatric surgery in obese women of reproductive age improves conditions that underlie fertility and pregnancy outcomes: retrospective cohort study of UK national bariatric surgery registry (NBSR). Obes Surg 26(12):2837–2842. https://doi.org/10.1007/s11695-016-2202-4
Escobar-Morreale HF, Santacruz E, Luque-Ramirez M, Botella Carretero JI (2017) Prevalence of ‘obesity-associated gonadal dysfunction’ in severely obese men and women and its resolution after bariatric surgery: a systematic review and meta-analysis. Hum Reprod Update 23(4):390–408. https://doi.org/10.1093/humupd/dmx012
Vincentelli C, Maraninchi M, Valero R, Beliard S, Maurice F, Emungania O, Berthet B, Lombard E, Dutour A, Gaborit B, Courbiere B (2018) One-year impact of bariatric surgery on serum anti-Mullerian-hormone levels in severely obese women. J Assist Reprod Genet. https://doi.org/10.1007/s10815-018-1196-3
Johansson K, Cnattingius S, Naslund I, Roos N, Trolle Lagerros Y, Granath F, Stephansson O, Neovius M (2015) Outcomes of pregnancy after bariatric surgery. N Engl J Med 372(9):814–824. https://doi.org/10.1056/NEJMoa1405789
Cruz S, Matos A, da Cruz SP, Pereira S, Saboya C, Ramalho A (2017) Relationship between the nutritional status of vitamin A per trimester of pregnancy with maternal anthropometry and anemia after Roux-en-Y gastric bypass. Nutrients. https://doi.org/10.3390/nu9090989
Gimenes JC, Nicoletti CF, de Souza Pinhel MA, de Oliveira BAP, Salgado Junior W, Marchini JS, Nonino CB (2017) Pregnancy after Roux en Y gastric bypass: nutritional and biochemical aspects. Obes Surg 27(7):1815–1821. https://doi.org/10.1007/s11695-017-2558-0
Smith J, Cianflone K, Biron S, Hould FS, Lebel S, Marceau S, Lescelleur O, Biertho L, Simard S, Kral JG, Marceau P (2009) Effects of maternal surgical weight loss in mothers on intergenerational transmission of obesity. J Clin Endocrinol Metab 94(11):4275–4283. https://doi.org/10.1210/jc.2009-0709
Grayson BE, Schneider KM, Woods SC, Seeley RJ (2013) Improved rodent maternal metabolism but reduced intrauterine growth after vertical sleeve gastrectomy. Sci Transl Med 5(199):199ra112. https://doi.org/10.1126/scitranslmed.3006505
Jans G, Matthys C, Bogaerts A, Lannoo M, Verhaeghe J, Van der Schueren B, Devlieger R (2015) Maternal micronutrient deficiencies and related adverse neonatal outcomes after bariatric surgery: a systematic review. Adv Nutr 6(4):420–429. https://doi.org/10.3945/an.114.008086
Rubino F, Forgione A, Cummings DE, Vix M, Gnuli D, Mingrone G, Castagneto M, Marescaux J (2006) The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. Ann Surg 244(5):741–749. https://doi.org/10.1097/01.sla.0000224726.61448.1b
Karra E, Yousseif A, Batterham RL (2010) Mechanisms facilitating weight loss and resolution of type 2 diabetes following bariatric surgery. TEM 21(6):337–344. https://doi.org/10.1016/j.tem.2010.01.006
Hao Z, Townsend RL, Mumphrey MB, Morrison CD, Munzberg H, Berthoud HR (2017) RYGB Produces more sustained body weight loss and improvement of glycemic control compared with VSG in the diet-induced obese mouse model. Obes Surg 27(9):2424–2433. https://doi.org/10.1007/s11695-017-2660-3
Blanchard C, Moreau F, Ayer A, Toque L, Garcon D, Arnaud L, Borel F, Aguesse A, Croyal M, Krempf M, Prieur X, Neunlist M, Cariou B, Le May C (2018) Roux-en-Y gastric bypass reduces plasma cholesterol in diet-induced obese mice by affecting trans-intestinal cholesterol excretion and intestinal cholesterol absorption. Int J Obes 42(3):552–560. https://doi.org/10.1038/ijo.2017.232
Sampey BP, Vanhoose AM, Winfield HM, Freemerman AJ, Muehlbauer MJ, Fueger PT, Newgard CB, Makowski L (2011) Cafeteria diet is a robust model of human metabolic syndrome with liver and adipose inflammation: comparison to high-fat diet. Obesity 19(6):1109–1117. https://doi.org/10.1038/oby.2011.18
Ebertz CE, Bonfleur ML, Bertasso IM, Mendes MC, Lubaczeuski C, Araujo AC, Paes AM, de Amorim EM, Balbo SL (2014) Duodenal jejunal bypass attenuates non-alcoholic fatty liver disease in western diet-obese rats. Acta Cirurgica Brasileira 29(9):609–614
Bayol SA, Simbi BH, Stickland NC (2005) A maternal cafeteria diet during gestation and lactation promotes adiposity and impairs skeletal muscle development and metabolism in rat offspring at weaning. J Physiol 567(Pt 3):951–961. https://doi.org/10.1113/jphysiol.2005.088989
Shelley P, Martin-Gronert MS, Rowlerson A, Poston L, Heales SJ, Hargreaves IP, McConnell JM, Ozanne SE, Fernandez-Twinn DS (2009) Altered skeletal muscle insulin signaling and mitochondrial complex II–III linked activity in adult offspring of obese mice. Am J Physiol Regul Integr Comp Physiol 297(3):R675–R681. https://doi.org/10.1152/ajpregu.00146.2009
Pound LD, Comstock SM, Grove KL (2014) Consumption of a Western-style diet during pregnancy impairs offspring islet vascularization in a Japanese macaque model. Am J Physiol Endocrinol Metab 307(1):E115–E123. https://doi.org/10.1152/ajpendo.00131.2014
Hao Z, Zhao Z, Berthoud HR, Ye J (2013) Development and verification of a mouse model for Roux-en-Y gastric bypass surgery with a small gastric pouch. PLoS One 8(1):e52922. https://doi.org/10.1371/journal.pone.0052922
Lubaczeuski C, Balbo SL, Ribeiro RA, Vettorazzi JF, Santos-Silva JC, Carneiro EM, Bonfleur ML (2015) Vagotomy ameliorates islet morphofunction and body metabolic homeostasis in MSG-obese rats. Braz J Med Biol Res 48(5):447–457. https://doi.org/10.1590/1414-431x20144340
Duivenvoorden I, Teusink B, Rensen PC, Romijn JA, Havekes LM, Voshol PJ (2005) Apolipoprotein C3 deficiency results in diet-induced obesity and aggravated insulin resistance in mice. Diabetes 54(3):664–671
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254
Ribeiro RA, Vanzela EC, Oliveira CA, Bonfleur ML, Boschero AC, Carneiro EM (2010) Taurine supplementation: involvement of cholinergic/phospholipase C and protein kinase A pathways in potentiation of insulin secretion and Ca2+ handling in mouse pancreatic islets. Br J Nutr 104(8):1148–1155. https://doi.org/10.1017/S0007114510001820
Quevedo MDP, Palermo M, Serra E, Ackermann MA (2017) Metabolic surgery: gastric bypass for the treatment of type 2 diabetes mellitus. Transl Gastroenterol Hepatol 2:58. https://doi.org/10.21037/tgh.2017.05.10
Balbo SL, Ribeiro RA, Mendes MC, Lubaczeuski C, Maller AC, Carneiro EM, Bonfleur ML (2016) Vagotomy diminishes obesity in cafeteria rats by decreasing cholinergic potentiation of insulin release. J Physiol Biochem 72(4):625–633. https://doi.org/10.1007/s13105-016-0501-9
Johnson AR, Wilkerson MD, Sampey BP, Troester MA, Hayes DN, Makowski L (2016) Cafeteria diet-induced obesity causes oxidative damage in white adipose. Biochem Biophys Res Commun 473(2):545–550. https://doi.org/10.1016/j.bbrc.2016.03.113
Meirelles K, Ahmed T, Culnan DM, Lynch CJ, Lang CH, Cooney RN (2009) Mechanisms of glucose homeostasis after Roux-en-Y gastric bypass surgery in the obese, insulin-resistant Zucker rat. Ann Surg 249(2):277–285. https://doi.org/10.1097/SLA.0b013e3181904af0
Liu Y, Zhou Y, Wang Y, Geng D, Liu J (2011) Roux-en-Y gastric bypass-induced improvement of glucose tolerance and insulin resistance in type 2 diabetic rats are mediated by glucagon-like peptide-1. Obes Surg 21(9):1424–1431. https://doi.org/10.1007/s11695-011-0388-z
Zhang S, Guo W, Wu J, Gong L, Li Q, Xiao X, Zhang J, Wang Z (2017) Increased beta-cell mass in obese rats after gastric bypass: a potential mechanism for improving glycemic control. Med Sci Monit Int Med J Exp Clin Res 23:2151–2158
Cummings BP, Graham JL, Stanhope KL, Chouinard ML, Havel PJ (2013) Maternal ileal interposition surgery confers metabolic improvements to offspring independent of effects on maternal body weight in UCD-T2DM rats. Obes Surg 23(12):2042–2049. https://doi.org/10.1007/s11695-013-1076-y
Kral JG, Biron S, Simard S, Hould FS, Lebel S, Marceau S, Marceau P (2006) Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2–18 years. Pediatrics 118(6):e1644–e1649. https://doi.org/10.1542/peds.2006-1379
Griffin IJ (2015) Catch-up growth: basic mechanisms. In: Embleton ND, Katz J, Ziegler EE (eds) Low-birthweight baby: born too soon or too small. Nestec Ltd, Vevey/S Karger AG, Basel, vol 81, pp 87–97. https://doi.org/10.1159/000365806
Manning BD, Toker A (2017) AKT/PKB signaling: navigating the network. Cell 169(3):381–405. https://doi.org/10.1016/j.cell.2017.04.001
Thompson N, Huber K, Bedurftig M, Hansen K, Miles-Chan J, Breier BH (2014) Metabolic programming of adipose tissue structure and function in male rat offspring by prenatal undernutrition. Nutr Metab 11(1):50. https://doi.org/10.1186/1743-7075-11-50
Cerf ME (2015) High fat programming of beta cell compensation, exhaustion, death and dysfunction. Pediatr Diabetes 16(2):71–78. https://doi.org/10.1111/pedi.12137
Ong TP, Ozanne SE (2015) Developmental programming of type 2 diabetes: early nutrition and epigenetic mechanisms. Curr Opin Clin Nutr Metab Care 18(4):354–360. https://doi.org/10.1097/MCO.0000000000000177
Comstock SM, Pound LD, Bishop JM, Takahashi DL, Kostrba AM, Smith MS, Grove KL (2012) High-fat diet consumption during pregnancy and the early post-natal period leads to decreased alpha cell plasticity in the nonhuman primate. Mol Metab 2(1):10–22. https://doi.org/10.1016/j.molmet.2012.11.001
Guenard F, Deshaies Y, Cianflone K, Kral JG, Marceau P, Vohl MC (2013) Differential methylation in glucoregulatory genes of offspring born before vs. after maternal gastrointestinal bypass surgery. Proc Natl Acad Sci USA 110(28):11439–11444. https://doi.org/10.1073/pnas.1216959110
Benatti RO, Melo AM, Borges FO, Ignacio-Souza LM, Simino LA, Milanski M, Velloso LA, Torsoni MA, Torsoni AS (2014) Maternal high-fat diet consumption modulates hepatic lipid metabolism and microRNA-122 (miR-122) and microRNA-370 (miR-370) expression in offspring. Br J Nutr 111(12):2112–2122. https://doi.org/10.1017/S0007114514000579
Wankhade UD, Zhong Y, Kang P, Alfaro M, Chintapalli SV, Thakali KM, Shankar K (2017) Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations. PLoS One 12(4):e0175675. https://doi.org/10.1371/journal.pone.0175675
We are grateful to Assis Roberto Escher for animal care and the graduate student Gabriela Alves Bronczek for all their help with experiments.
This study forms part of the MSc thesis of C. B. Pietrobon and was supported by Grants from Fundação Araucária (155/2013), Conselho Nacional para o Desenvolvimento Científico e Tecnológico (CNPq, Processo no. 447190/2014-8), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, PROAP, no.: 817693/2015) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 2015/12611-0).
Conflict of interest
All authors who contributed to the study state that there was no conflict of interest.
About this article
Cite this article
Pietrobon, C.B., Bertasso, I.M., Ribeiro, R.A. et al. Maternal Roux-en-Y gastric bypass impairs insulin action and endocrine pancreatic function in male F1 offspring. Eur J Nutr 59, 1067–1079 (2020). https://doi.org/10.1007/s00394-019-01968-9
- Bariatric operation
- Insulin resistance
- Insulin secretion
- Maternal programming
- Metabolic imprinting