Maternal Roux-en-Y gastric bypass impairs insulin action and endocrine pancreatic function in male F1 offspring
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.
KeywordsBariatric operation Insulin resistance Insulin secretion Maternal programming Metabolic imprinting Obesity
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).
Compliance with ethical standards
Conflict of interest
All authors who contributed to the study state that there was no conflict of interest.
- 1.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 CrossRefGoogle Scholar
- 6.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 CrossRefGoogle Scholar
- 7.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 CrossRefGoogle Scholar
- 10.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) 9:21–29Google Scholar
- 11.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 CrossRefGoogle Scholar
- 12.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 CrossRefGoogle Scholar
- 13.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 Google Scholar
- 17.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 CrossRefGoogle Scholar
- 20.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 CrossRefGoogle Scholar
- 22.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 CrossRefGoogle Scholar
- 23.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 CrossRefGoogle Scholar
- 24.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 CrossRefGoogle Scholar
- 27.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 CrossRefGoogle Scholar
- 33.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 CrossRefGoogle Scholar
- 39.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 23:2151–2158Google Scholar
- 40.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 CrossRefGoogle Scholar
- 42.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
- 47.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 CrossRefGoogle Scholar
- 48.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 CrossRefGoogle Scholar
- 49.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 CrossRefGoogle Scholar
- 50.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 CrossRefGoogle Scholar