vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-24-33vavilov-4142Research ArticleРЕПРОДУКТИВНЫЕ ТЕХНОЛОГИИPHYSIOLOGICAL GENETICSВведение лептина беременным мышам влияет на экспрессию генов у плодов и адаптацию к сладкой и жирной пище у взрослых потомков разного полаInfluence of leptin administration to pregnant mice on fetal gene expression and adaptation to sweet and fatty food in adult offspring of different sexesДенисоваЕ. И.DenisovaE. I.

Новосибирск

Novosibirsk

МакароваЕ. Н.MakarovaE. N.

Новосибирск

Novosibirsk

enmakarova@gmail.comФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian Federation202430052024283288298Copyright © Денисова Е.И., Макарова Е.Н., 20242024Денисова Е.И., Макарова Е.Н.Denisova E.I., Makarova E.N.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4142

Повышенный уровень лептина в период беременности у самок мышей оказывает благоприятное действие на метаболические показатели их зрелого потомства при потреблении последним высококалорийной пищи, и это влияние может зависеть от пола. Молекулярные механизмы, опосредующие программирующее действие лептина, неизвестны. Целью представленной работы было изучение программирующего действия материнского лептина на сигнальную функцию плацент и печени плодов, а также на адаптацию к высококалорийной диете у потомства в зависимости от пола. Самкам мышей линии C57BL/6J вводили лептин в середине беременности. В конце беременности в плацентах, мозге и печени плодов оценивали экспрессию генов. У взрослого потомства обоего пола оценивали метаболические показатели и экспрессию генов в печени, буром жире и гипоталамусе после двухнедельного потребления стандартной либо сладко-жирной диеты (СЖД: гранулы стандартного корма, сало, сладкое печенье). У самок наблюдался более низкий уровень лептина, глюкозы, триглицеридов и холестерина в крови, чем у самцов. Потребление СЖД увеличивало экспрессию гена Ucp1 в буром жире у самок, тогда как у самцов накапливался жир, снижались уровень триглицеридов в крови и экспрессия гена Fasn в печени. Введение лептина матерям увеличивало экспрессию генов Igf1 и Dnmt3b в печени плодов, снижало скорость роста после отъема от матери и повышало экспрессию Crh в гипоталамусе в ответ на СЖД у взрослых потомков обоих полов. Только у самцов введение лептина матерям снижало экспрессию генов Fasn и Gck в печени, увеличивало жировую массу, уровни глюкозы, триглицеридов и холестерина в крови, а также экспрессию гена Dmnt3a в печени плодов. Полученные результаты позволяют предположить, что влияние материнского лептина на экспрессию генов, кодирующих факторы роста и ДНКметилтрансферазы в печени плодов, может опосредовать его программирующий эффект на метаболический фенотип потомства.

Elevated leptin in pregnant mice improves metabolism in offspring fed high-calorie diet and its influence may be sex-specific. Molecular mechanisms mediating leptin programming action are unknown. We aimed to investigate programming actions of maternal leptin on the signaling function of the placenta and fetal liver and on adaptation to high-calorie diet in male and female offspring. Female C57BL/6J mice received leptin injections in mid-pregnancy. Gene expression was assessed in placentas and in the fetal brain and liver at the end of pregnancy. Metabolic parameters and gene expression in the liver, brown fat and hypothalamus were assessed in adult male and female offspring that had consumed sweet and fatty diet (SFD: chow, lard, sweet biscuits) for 2 weeks. Females had lower blood levels of leptin, glucose, triglycerides and cholesterol than males. Consuming SFD, females had increased Ucp1 expression in brown fat, while males had accumulated fat, decreased blood triglycerides and liver Fasn expression. Leptin administration to mothers increased Igf1 and Dnmt3b expression in fetal liver, decreased post-weaning growth rate, and increased hypothalamic Crh expression in response to SFD in both sexes. Only in male offspring this administration decreased expression of Fasn and Gck in the mature liver, increased fat mass, blood levels of glucose, triglycerides and cholesterol and Dmnt3a expression in the fetal liver. The results suggest that the influence of maternal leptin on the expression of genes encoding growth factors and DNA methyltransferases in the fetal liver may mediate its programming effect on offspring metabolic phenotypes.

адаптация к высококалорийной пищепрограммирование развитиялептинмышибеременностьadaptation to high-calorie fooddevelopmental programmingleptinmicepregnancyThis research was funded by RFBR, grant number 20-315-90071, and Budget grant FWNR-2022-0021.ReferencesAkieda-Asai S., Koda S., Sugiyama M., Hasegawa K., Furuya M., Miyazato M., Date Y. Metabolic features of rats resistant to a high-fat diet. Obes. Res. Clin. Pract. 2013;7(4):e243-e250. DOI 10.1016/j.orcp.2013.01.004Akieda-Asai S., Koda S., Sugiyama M., Hasegawa K., Furuya M., Miyazato M., Date Y. Metabolic features of rats resistant to a high-fat diet. Obes. Res. Clin. Pract. 2013;7(4):e243-e250. DOI 10.1016/j.orcp.2013.01.004Andrich D.E., Melbouci L., Ou Y., Leduc-Gaudet J.-P., Chabot F., Lalonde F., Lira F.S., Gaylinn B.D., Gouspillou G., Danialou G., Comtois A.-S., St-Pierre D.H. Altered feeding behaviors and adiposity precede observable weight gain in young rats submitted to a short­term high­fat diet. J. Nutr. Metab. 2018;2018:1498150. DOI 10.1155/2018/1498150Andrich D.E., Melbouci L., Ou Y., Leduc-Gaudet J.-P., Chabot F., Lalonde F., Lira F.S., Gaylinn B.D., Gouspillou G., Danialou G., Comtois A.-S., St-Pierre D.H. Altered feeding behaviors and adiposity precede observable weight gain in young rats submitted to a short­term high­fat diet. J. Nutr. Metab. 2018;2018:1498150. DOI 10.1155/2018/1498150Candler T., Kühnen P., Prentice A.M., Silver M. Epigenetic regulation of POMC; implications for nutritional programming, obesity and metabolic disease. Front. Neuroendocrinol. 2019;54:100773. DOI 10.1016/j.yfrne.2019.100773Candler T., Kühnen P., Prentice A.M., Silver M. Epigenetic regulation of POMC; implications for nutritional programming, obesity and metabolic disease. Front. Neuroendocrinol. 2019;54:100773. DOI 10.1016/j.yfrne.2019.100773Casimiro I., Stull N.D., Tersey S.A., Mirmira R.G. Phenotypic sexual dimorphism in response to dietary fat manipulation in C57BL/6J mice. J. Diabetes Complications. 2021;35(2):107795. DOI 10.1016/j.jdiacomp.2020.107795Casimiro I., Stull N.D., Tersey S.A., Mirmira R.G. Phenotypic sexual dimorphism in response to dietary fat manipulation in C57BL/6J mice. J. Diabetes Complications. 2021;35(2):107795. DOI 10.1016/j.jdiacomp.2020.107795Cone R.D. Anatomy and regulation of the central melanocortin system. Nat. Neurosci. 2005;8(5):571-578. DOI 10.1038/nn1455Cone R.D. Anatomy and regulation of the central melanocortin system. Nat. Neurosci. 2005;8(5):571-578. DOI 10.1038/nn1455Dearden L., Ozanne S.E. Early life origins of metabolic disease: developmental programming of hypothalamic pathways controlling energy homeostasis. Front. Neuroendocrinol. 2015;39:3-16. DOI 10.1016/j.yfrne.2015.08.001Dearden L., Ozanne S.E. Early life origins of metabolic disease: developmental programming of hypothalamic pathways controlling energy homeostasis. Front. Neuroendocrinol. 2015;39:3-16. DOI 10.1016/j.yfrne.2015.08.001Dearden L., Bouret S.G., Ozanne S.E. Sex and gender differences in developmental programming of metabolism. Mol. Metab. 2018;15: 8-19. DOI 10.1016/j.molmet.2018.04.007Dearden L., Bouret S.G., Ozanne S.E. Sex and gender differences in developmental programming of metabolism. Mol. Metab. 2018;15: 8-19. DOI 10.1016/j.molmet.2018.04.007Denisova E.I., Savinkova M.M., Makarova E.N. Influence of leptin administration to pregnant female mice on obesity development, taste preferences, and gene expression in the liver and muscles of their male and female offspring. Vavilov J. Genet. Breed. 2021;25(6): 669-676. DOI 10.18699/VJ21.076Denisova E.I., Savinkova M.M., Makarova E.N. Influence of leptin administration to pregnant female mice on obesity development, taste preferences, and gene expression in the liver and muscles of their male and female offspring. Vavilov J. Genet. Breed. 2021;25(6): 669-676. DOI 10.18699/VJ21.076Duca F.A., Sakar Y., Lepage P., Devime F., Langelier B., Doré J., Covasa M. Replication of obesity and associated signaling pathways through transfer of microbiota from obese­prone rats. Diabetes. 2014;63(5):1624-1636. DOI 10.2337/db13-1526Duca F.A., Sakar Y., Lepage P., Devime F., Langelier B., Doré J., Covasa M. Replication of obesity and associated signaling pathways through transfer of microbiota from obese­prone rats. Diabetes. 2014;63(5):1624-1636. DOI 10.2337/db13-1526Even P.C. Identification of behavioral and metabolic factors predicting adiposity sensitivity to both high fat and high carbohydrate diets in rats. Front. Physiol. 2011;2:96. DOI 10.3389/fphys.2011.00096Even P.C. Identification of behavioral and metabolic factors predicting adiposity sensitivity to both high fat and high carbohydrate diets in rats. Front. Physiol. 2011;2:96. DOI 10.3389/fphys.2011.00096Flippo K.H., Potthoff M.J. Metabolic messengers: FGF21. Nat. Metab. 2021;3(3):309-317. DOI 10.1038/s42255-021-00354-2Flippo K.H., Potthoff M.J. Metabolic messengers: FGF21. Nat. Metab. 2021;3(3):309-317. DOI 10.1038/s42255-021-00354-2Freire-Regatillo A., Fernández-Gómez M.J., Díaz F., Barrios V., Sánchez-Jabonero I., Frago L.M., Argente J., García-Segura L.M., Chowen J.A. Sex differences in the peripubertal response to a shortterm, high-fat diet intake. J. Neuroendocrinol. 2020;32(1):e12756. DOI 10.1111/jne.12756Freire-Regatillo A., Fernández-Gómez M.J., Díaz F., Barrios V., Sánchez-Jabonero I., Frago L.M., Argente J., García-Segura L.M., Chowen J.A. Sex differences in the peripubertal response to a shortterm, high-fat diet intake. J. Neuroendocrinol. 2020;32(1):e12756. DOI 10.1111/jne.12756Hacker A., Capel B., Goodfellow P., Lovell-Badge R. Expression of Sry, the mouse sex determining gene. Development. 1995;121(6): 1603-1614. DOI 10.1242/dev.121.6.1603Hacker A., Capel B., Goodfellow P., Lovell-Badge R. Expression of Sry, the mouse sex determining gene. Development. 1995;121(6): 1603-1614. DOI 10.1242/dev.121.6.1603Hattori Y., Takeda T., Fujii M., Taura J., Yamada H., Ishii Y. Attenuation of growth hormone production at the fetal stage is critical for dioxin-induced developmental disorder in rat offspring. Biochem. Phar macol. 2021;186:114495. DOI 10.1016/j.bcp.2021.114495Hattori Y., Takeda T., Fujii M., Taura J., Yamada H., Ishii Y. Attenuation of growth hormone production at the fetal stage is critical for dioxin-induced developmental disorder in rat offspring. Biochem. Phar macol. 2021;186:114495. DOI 10.1016/j.bcp.2021.114495Hellström A., Ley D., Hansen-Pupp I., Hallberg B., Löfqvist C., Marter L., Weissenbruch M., Ramenghi L.A., Beardsall K., Dunger D., Hård A., Smith L.E.H. Insulin-like growth factor 1 has multisystem effects on foetal and preterm infant development. Acta Paediatr. 2016;105(6):576-586. DOI 10.1111/apa.13350Hellström A., Ley D., Hansen-Pupp I., Hallberg B., Löfqvist C., Marter L., Weissenbruch M., Ramenghi L.A., Beardsall K., Dunger D., Hård A., Smith L.E.H. Insulin-like growth factor 1 has multisystem effects on foetal and preterm infant development. Acta Paediatr. 2016;105(6):576-586. DOI 10.1111/apa.13350Hwang L.-L., Wang C.-H., Li T.-L., Chang S.-D., Lin L.-C., Chen C.- P., Chen C.-T., Liang K.-C., Ho I.-K., Yang W.-S., Chiou L.-C. Sex differences in high­fat diet­induced obesity, metabolic alterations and learning, and synaptic plasticity deficits in mice. Obesity. 2010; 18(3):463-469. DOI 10.1038/oby.2009.273Hwang L.-L., Wang C.-H., Li T.-L., Chang S.-D., Lin L.-C., Chen C.- P., Chen C.-T., Liang K.-C., Ho I.-K., Yang W.-S., Chiou L.-C. Sex differences in high­fat diet­induced obesity, metabolic alterations and learning, and synaptic plasticity deficits in mice. Obesity. 2010; 18(3):463-469. DOI 10.1038/oby.2009.273Ishii Y., Bouret S.G. Embryonic birthdate of hypothalamic leptin-activated neurons in mice. Endocrinology. 2012;153(8):3657-3667. DOI 10.1210/en.2012-1328Ishii Y., Bouret S.G. Embryonic birthdate of hypothalamic leptin-activated neurons in mice. Endocrinology. 2012;153(8):3657-3667. DOI 10.1210/en.2012-1328Jurkowska R.Z., Jurkowski T.P., Jeltsch A. Structure and function of mammalian DNA methyltransferases. Chembiochem. 2011;12(2): 206-222. DOI 10.1002/cbic.201000195Jurkowska R.Z., Jurkowski T.P., Jeltsch A. Structure and function of mammalian DNA methyltransferases. Chembiochem. 2011;12(2): 206-222. DOI 10.1002/cbic.201000195Kakall Z.M., Gopalasingam G., Herzog H., Zhang L. Dynamic regional alterations in mouse brain neuronal activity following short­term changes in energy balance. Obesity. 2021;29(10):1650-1663. DOI 10.1002/oby.23253Kakall Z.M., Gopalasingam G., Herzog H., Zhang L. Dynamic regional alterations in mouse brain neuronal activity following short­term changes in energy balance. Obesity. 2021;29(10):1650-1663. DOI 10.1002/oby.23253Magnuson M.A., She P., Shiota M. Gene-altered mice and metabolic flux control. J. Biol. Chem. 2003;278(35):32485-32488. DOI 10.1074/jbc.R300020200Magnuson M.A., She P., Shiota M. Gene-altered mice and metabolic flux control. J. Biol. Chem. 2003;278(35):32485-32488. DOI 10.1074/jbc.R300020200Makarova E.N., Chepeleva E.V., Panchenko P.E., Bazhan N.M. Influence of abnormally high leptin levels during pregnancy on metabolic phenotypes in progeny mice. Am. J. Physiol. Integr. Comp. Physiol. 2013;305(11):R1268-R1280. DOI 10.1152/ajpregu.00162.2013Makarova E.N., Chepeleva E.V., Panchenko P.E., Bazhan N.M. Influence of abnormally high leptin levels during pregnancy on metabolic phenotypes in progeny mice. Am. J. Physiol. Integr. Comp. Physiol. 2013;305(11):R1268-R1280. DOI 10.1152/ajpregu.00162.2013Massa M.L., Gagliardino J.J., Francini F. Liver glucokinase: an overview on the regulatorymechanisms of its activity. IUBMB Life. 2011;63(1):1-6. DOI 10.1002/iub.411Massa M.L., Gagliardino J.J., Francini F. Liver glucokinase: an overview on the regulatorymechanisms of its activity. IUBMB Life. 2011;63(1):1-6. DOI 10.1002/iub.411Morton G.J. Hypothalamic leptin regulation of energy homeostasis and glucose metabolism. J. Physiol. 2007;583(2):437-443. DOI 10.1113/jphysiol.2007.135590Morton G.J. Hypothalamic leptin regulation of energy homeostasis and glucose metabolism. J. Physiol. 2007;583(2):437-443. DOI 10.1113/jphysiol.2007.135590Nawathe A.R., Christian M., Kim S.H., Johnson M., Savvidou M.D., Terzidou V. Insulin-like growth factor axis in pregnancies affected by fetal growth disorders. Clin. Epigenetics. 2016;8(1):11. DOI 10.1186/s13148-016-0178-5Nawathe A.R., Christian M., Kim S.H., Johnson M., Savvidou M.D., Terzidou V. Insulin-like growth factor axis in pregnancies affected by fetal growth disorders. Clin. Epigenetics. 2016;8(1):11. DOI 10.1186/s13148-016-0178-5Nilsson C., Swolin-Eide D., Ohlsson C., Eriksson E., Ho H., Bjorntorp P., Holmang A. Reductions in adipose tissue and skeletal growth in rat adult offspring after prenatal leptin exposure. J. Endocrinol. 2003;176(1):13-21. DOI 10.1677/joe.0.1760013Nilsson C., Swolin-Eide D., Ohlsson C., Eriksson E., Ho H., Bjorntorp P., Holmang A. Reductions in adipose tissue and skeletal growth in rat adult offspring after prenatal leptin exposure. J. Endocrinol. 2003;176(1):13-21. DOI 10.1677/joe.0.1760013Niu X., Wu X., Ying A., Shao B., Li X., Zhang W., Lin C., Lin Y. Maternal high fat diet programs hypothalamic­pituitary­adrenal function in adult rat offspring. Psychoneuroendocrinology. 2019;102:128138. DOI 10.1016/j.psyneuen.2018.12.003Niu X., Wu X., Ying A., Shao B., Li X., Zhang W., Lin C., Lin Y. Maternal high fat diet programs hypothalamic­pituitary­adrenal function in adult rat offspring. Psychoneuroendocrinology. 2019;102:128138. DOI 10.1016/j.psyneuen.2018.12.003Petry C.J., Evans M.L., Wingate D.L., Ong K.K., Reik W., Constância M., Dunger D.B. Raised late pregnancy glucose concentrations in mice carrying pups with targeted disruption of H19Δ13. Diabetes. 2010;59(1):282-286. DOI 10.2337/db09-0757Petry C.J., Evans M.L., Wingate D.L., Ong K.K., Reik W., Constância M., Dunger D.B. Raised late pregnancy glucose concentrations in mice carrying pups with targeted disruption of H19Δ13. Diabetes. 2010;59(1):282-286. DOI 10.2337/db09-0757Pollock K.E., Stevens D., Pennington K.A., Thaisrivongs R., Kaiser J., Ellersieck M.R., Miller D.K., Schulz L.C. Hyperleptinemia during pregnancy decreases adult weight of offspring and is associated with increased offspring locomotor activity in mice. Endocrinology. 2015;156(10):3777-3790. DOI 10.1210/en.2015-1247Pollock K.E., Stevens D., Pennington K.A., Thaisrivongs R., Kaiser J., Ellersieck M.R., Miller D.K., Schulz L.C. Hyperleptinemia during pregnancy decreases adult weight of offspring and is associated with increased offspring locomotor activity in mice. Endocrinology. 2015;156(10):3777-3790. DOI 10.1210/en.2015-1247Radahmadi M., Izadi M.S., Rayatpour A., Ghasemi M. Comparative study of CRH microinjections into PVN and CeA nuclei on food intake, ghrelin, leptin, and glucose levels in acute stressed rats. Basic Clin. Neurosci. J. 2021;12(1):133-148. DOI 10.32598/bcn.12.1.2346.1Radahmadi M., Izadi M.S., Rayatpour A., Ghasemi M. Comparative study of CRH microinjections into PVN and CeA nuclei on food intake, ghrelin, leptin, and glucose levels in acute stressed rats. Basic Clin. Neurosci. J. 2021;12(1):133-148. DOI 10.32598/bcn.12.1.2346.1Reynolds C.M., Segovia S.A., Vickers M.H. Experimental models of maternal obesity and neuroendocrine programming of metabolic disorders in offspring. Front. Endocrinol. 2017;8:245. DOI 10.3389/fendo.2017.00245Reynolds C.M., Segovia S.A., Vickers M.H. Experimental models of maternal obesity and neuroendocrine programming of metabolic disorders in offspring. Front. Endocrinol. 2017;8:245. DOI 10.3389/fendo.2017.00245Richard D., Huang Q., Timofeeva E. The corticotropin-releasing hormone system in the regulation of energy balance in obesity. Int. J. Obes. Relat. Metab. Disord. 2000;24(S2):S36-S39. DOI 10.1038/sj.ijo.0801275Richard D., Huang Q., Timofeeva E. The corticotropin-releasing hormone system in the regulation of energy balance in obesity. Int. J. Obes. Relat. Metab. Disord. 2000;24(S2):S36-S39. DOI 10.1038/sj.ijo.0801275Schoonejans J.M., Blackmore H.L., Ashmore T.J., Aiken C.E., Fernandez-Twinn D.S., Ozanne S.E. Maternal metformin intervention during obese glucose-intolerant pregnancy affects adiposity in young adult mouse offspring in a sex-specific manner. Int. J. Mol. Sci. 2021;22(15):8104. DOI 10.3390/ijms22158104Schoonejans J.M., Blackmore H.L., Ashmore T.J., Aiken C.E., Fernandez-Twinn D.S., Ozanne S.E. Maternal metformin intervention during obese glucose-intolerant pregnancy affects adiposity in young adult mouse offspring in a sex-specific manner. Int. J. Mol. Sci. 2021;22(15):8104. DOI 10.3390/ijms22158104Shrestha D., Ouidir M., Workalemahu T., Zeng X., Tekola-Ayele F. Placental DNA methylation changes associated with maternal prepregnancy BMI and gestational weight gain. Int. J. Obes. 2020;44(6): 1406-1416. DOI 10.1038/s41366-020-0546-2Shrestha D., Ouidir M., Workalemahu T., Zeng X., Tekola-Ayele F. Placental DNA methylation changes associated with maternal prepregnancy BMI and gestational weight gain. Int. J. Obes. 2020;44(6): 1406-1416. DOI 10.1038/s41366-020-0546-2So M., Gaidhu M.P., Maghdoori B., Ceddia R.B. Analysis of timedependent adaptations in whole­body energy balance in obesity induced by high­fat diet in rats. Lipids Health Dis. 2011;10(1):99. DOI 10.1186/1476-511X-10-99So M., Gaidhu M.P., Maghdoori B., Ceddia R.B. Analysis of timedependent adaptations in whole­body energy balance in obesity induced by high­fat diet in rats. Lipids Health Dis. 2011;10(1):99. DOI 10.1186/1476-511X-10-99Stocker C.J., Cawthorne M.A. The influence of leptin on early life programming of obesity. Trends Biotechnol. 2008;26(10):545-551. DOI 10.1016/j.tibtech.2008.06.004Stocker C.J., Cawthorne M.A. The influence of leptin on early life programming of obesity. Trends Biotechnol. 2008;26(10):545-551. DOI 10.1016/j.tibtech.2008.06.004Talton O.O., Pennington K.A., Pollock K.E., Bates K., Ma L., Ellersieck M.R., Schulz L.C. Maternal hyperleptinemia improves offspring insulin sensitivity in mice. Endocrinology. 2016;157(7): 2636-2648. DOI 10.1210/en.2016-1039Talton O.O., Pennington K.A., Pollock K.E., Bates K., Ma L., Ellersieck M.R., Schulz L.C. Maternal hyperleptinemia improves offspring insulin sensitivity in mice. Endocrinology. 2016;157(7): 2636-2648. DOI 10.1210/en.2016-1039Voigt A., Agnew K., van Schothorst E.M., Keijer J., Klaus S. Shortterm, high fat feeding­induced changes in white adipose tissue gene expression are highly predictive for long-term changes. Mol. Nutr. Food Res. 2013;57(8):1423-1434. DOI 10.1002/mnfr.201200671Voigt A., Agnew K., van Schothorst E.M., Keijer J., Klaus S. Shortterm, high fat feeding­induced changes in white adipose tissue gene expression are highly predictive for long-term changes. Mol. Nutr. Food Res. 2013;57(8):1423-1434. DOI 10.1002/mnfr.201200671Xiagedeer B., Kang C., Hou X., Hu H., Xiao Q., Hao W. Chlormequat chloride promotes rat embryonic growth and GH-IGF-1 axis. Toxicology. 2020;429:152326. DOI 10.1016/j.tox.2019.152326Xiagedeer B., Kang C., Hou X., Hu H., Xiao Q., Hao W. Chlormequat chloride promotes rat embryonic growth and GH-IGF-1 axis. Toxicology. 2020;429:152326. DOI 10.1016/j.tox.2019.152326Yu P., Chen Y., Ge C., Wang H. Sexual dimorphism in placental development and its contribution to health and diseases. Crit. Rev. Toxicol. 2021;51(6):555-570. DOI 10.1080/10408444.2021.1977237Yu P., Chen Y., Ge C., Wang H. Sexual dimorphism in placental development and its contribution to health and diseases. Crit. Rev. Toxicol. 2021;51(6):555-570. DOI 10.1080/10408444.2021.1977237Zhu C., Xu Y., Jiang Z., Tian J.B., Cassidy R.M., Cai Z.L., Shu G., Xu Y., Xue M., Arenkiel B.R., Jiang Q., Tong Q. Disrupted hypothalamic CRH neuron responsiveness contributes to diet‐induced obesity. EMBO Rep. 2020;21(7):e49210. DOI 10.15252/embr.2019 49210Zhu C., Xu Y., Jiang Z., Tian J.B., Cassidy R.M., Cai Z.L., Shu G., Xu Y., Xue M., Arenkiel B.R., Jiang Q., Tong Q. Disrupted hypothalamic CRH neuron responsiveness contributes to diet‐induced obesity. EMBO Rep. 2020;21(7):e49210. DOI 10.15252/embr.2019 49210

The authors declare that there are no conflicts of interest present.