Effects of maternal high-fat diet and exercise intervention on insulin sensitivity and the hypothalamic arcuate nucleus in male offspring mice

doi:10.12307/2023.986

Abstract

Abstract: BACKGROUND: In the offspring of obese mothers, some metabolic genes are “silent” under certain environmental influences. These “silent” genes may be “awakened” under the acquired environment and then cause metabolic regulation disorders.
OBJECTIVE: In the case of offspring with different diets, to explore the metabolic genetic effects of long-term high-fat and exercise intervention in female mice.
METHODS: Seventy 3-week-old female C57BL/6 mice were divided into high-fat diet (HFD) and high-at exercise groups (high-fat diet+exercise, HFD-Ex), and they gave birth naturally after 16 weeks of intervention. After 4-week lactation, 16 male offspring mice from each group were randomly selected. Totally 32 offspring mice were randomly divided into 4 subgroups and given high-fat diet or standard chow diet for 6 weeks: HFD-HFD, HFD-Ex-HFD, HFD-standard chow diet, and HFD-Ex-standard chow diet. The offspring mice were subjected to glucose tolerance test and insulin tolerance test in the 10th week, followed by body composition analysis and sacrifice. Western blot was used to determine the level of p-Akt in the liver. Immunofluorescence of the hypothalamic arcuate nucleus was used to analyze the expression of neuropeptide Y and pro-opiomelanocortion.
RESULTS AND CONCLUSION: Under the high-fat diet, compared with the HFD group, the offspring of the HFD-Ex group had significantly improvements in glucose metabolism, body mass, and body composition (P < 0.05). Under the standard chow diet, compared with the HFD group, the expression of neuropeptide Y in the hypothalamic arcuate nucleus of the HFD-Ex group was significantly decreased (P < 0.05), and the expression of pro-opiomelanocortion was significantly up-regulated (P < 0.05). In the case of insulin (-), the expression of phosphorylated Akt (Ser473) protein in the liver showed no significant difference between the two groups, but in the case of insulin (+), there was a significant difference between the two groups (P < 0.05). In the high-fat diet mode, the metabolic protection effect of the maternal long-term exercise may gradually weaken with the prolongation of the offspring’s high-fat exposure; in the standard chow diet mode, the maternal long-term exercise can improve the central regulation of energy metabolism and insulin sensitivity of the male offspring.

Key words: insulin sensitivity, arcuate nucleus, appetite regulation, exercise intervention, high-fat diet, neuropeptide Y, pro-opiomelanocortion

CLC Number:

Zhu Xiaofeng, Chen Weiwei, Huang Jian. Effects of maternal high-fat diet and exercise intervention on insulin sensitivity and the hypothalamic arcuate nucleus in male offspring mice[J]. Chinese Journal of Tissue Engineering Research, 2024, 28(4): 556-561.

Figures/Tables 6

References

[1] BARKER DJP. The developmental origins of insulin resistance. Horm res. 2005;64 (Suppl 3):2-7.
[2] DRAKE AJ, REYNOLDS RM. Impact of maternal obesity on offspring obesity and cardiometabolic disease risk. Reproduction. 2010;140(3): 387-398.
[3] ZHU XF, YUN M, QUN Y, et al. Effects of high-fat diet and exercise intervention on the metabolism regulation of infant mice. Biomed Res Int. 2020;2020:2358391.
[4] ZHU XF, FU S, MA Y, et al. Long-term exercise improves metabolism during pregnancy in high-fat fed mice. Int J Clin Exp Med. 2019;12(6): 6828-6840.
[5] RAIPURIA M, BAHARI H, MORRIS MJ. Effects of maternal diet and exercise during pregnancy on glucose metabolism in skeletal muscle and fat of weanling rats. PloS One. 2015;10(4):e0120980.
[6] VEGA CC, REYES-CASTRO LA, BAUTISTA CJ, et al. Exercise in obese female rats has beneficial effects on maternal and male and female offspring metabolism. Int J Obes (Lond). 2015;39(4):712-719.
[7] KLEIN MO, MACKAY H, EDWARDS A, et al. Pomc and npy mrna expression during development is increased in rat offspring brain from mothers fed with a high fat diet. Int J Dev Neurosci. 2018;(64):14-20.
[8] LAING BT, DO K, MATSUBARA T, et al. Voluntary exercise improves hypothalamic and metabolic function in obese mice. J Endoc. 2016; 229(2):109-122.
[9] WU Z, XI P, ZHANG Y, et al. Lkb1 up-regulation inhibits hypothalamic inflamma-tion and attenuates diet-induced obesity in mice. Metabolism. 2021;116 (10): 154694.
[10] KOCH M, VARELA L, KIM JG, et al. Hypothalamic pomc neurons promote cannabinoid-induced feeding. Nature. 2015;519(7541):45-50.
[11] CQA B, XF C, DCA B. Pomc neurons dysfunction in diet-induced metabolic disease: Hallmark or mechanism of disease? Neuroscience. 2020;447:3-14.
[12] STUEBE AM, OKEN E, GILLMAN MW. Associations of diet and physical activity during pregnancy with risk for excessive gestational weight gain. Am J Obstet Gynecol. 2009;201(1):51-58.
[13] GENEST DS, FALCAO S, MICHEL C, et al. Exercise training promotes placental growth and development in an animal model of preeclampsia superimposed on chronic hypertension. Pregnancy hypertension. 2012;2(3):209-210.
[14] UEDA M, ADACHI Y, TANAKA M, et al. Association between mental health and physical activity during pregnancy. Maternal Health. 2012; 53(2):367-374.
[15] YOSHIFUMI T, DAISUKE A, KAZUSHIGE G, et al. High-intensity exercise causes greater irisin response compared with low-intensity exercise under similar energy consumption. Tohoku J Exp Med. 2014;233(2): 135-140.
[16] LAING BT, DO K, MATSUBARA T, et al.Voluntary exercise improves hypothalamic and metabolic function in obese mice. J Endocrinol. 2016;229(2):109-122.
[17] WASINSKI F, BACURAU RF, ESTRELA GR, et al. Exercise during pregnancy protects adult mouse offspring from diet-induced obesity. Nutr Metab (Lond). 2015;12:56.
[18] CARTER LG, NGO TENLEP SY, WOOLLETT LA, et al. Exercise improves glucose disposal and insulin signaling in pregnant mice fed a high fat diet. J Diabetes Metab. 2015;6(12):634.
[19] BARKER DJP, GLUCKMAN PD, GODFREY KM, et al. Fetal nutrition and cardiovascular disease in adult life. Lancet. 1993;341(8850):938-941.
[20] NG SF, LIN RC, LAYBUTT DR, et al. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature. 2010; 467(7318):963-966.
[21] FRANKE K, HARDER T, AERTS L, et al. Programming’ of orexigenic and anorexigenic hypothalamic neurons in offspring of treated and untreated diabetic mother rats. Brain Res. 2005;1031(2):276-283.
[22] SAFTLAS AF, LOGSDEN-SACKETT N, WANG W, et al. Work, leisure-time physical activity, and risk of preeclampsia and gestational hypertension. Am J Epidemiol. 2004;160(8):758-765.
[23] ZHENG X, NIU S. Leptin-induced basal Akt phosphorylation and its implication in exercise-mediated improvement of insulin sensitivity. Biochem Biophys Res Commun. 2018;496(1):37-43.
[24] HAJDUCH E, LITHERLAND GJ, HUNDA HS. Protein kinase B (PKB/Akt) — a key regulator of glucose transport? FEBS Lett. 2001;492(3):199-203.
[25] VENDRELL J, BROCH M, VILARRASA N, et al. Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: Relationships in obesity. Obes Res. 2012;12(6):962-971.
[26] EGGER G. Dousing our inflammatory environment(s): Is personal carbon trading an option for reducing obesity--and climate change? Obes Rev. 2010;9(5):456-463.
[27] TESSIER DR, FERRARO ZM, GRUSLIN A. Role of leptin in pregnancy: Consequences of maternal obesity. Placenta. 2013;34(3):205-211.
[28] GHERLAN I, VLADOIU S, ALEXIU F, et al. Adipocytokine profile and insulin resistance in childhood obesity. J Clin Med. 2012;7(3):205-213.
[29] TAMORI Y, KASUGA M. Obesity and insulin resistance. Nihon Rinsho. 2009;67(2):236-244.
[30] BIENSO RS, RINGHOLM S, KIILERICH K, et al. Glut4 and glycogen synthase are key players in bed rest-induced insulin resistance. Diabetes. 2012;61(5):1090-1099.
[31] SUN B, LIANG NC, EWALD ER, et al. Early postweaning exercise improves central leptin sensitivity in offspring of rat dams fed high-fat diet during pregnancy and lactation. Am J Physiol Regul Integr Comp Physiol. 2013;305(9 ):1076-1084.
[32] OKOROKOV PL, KALININ AL, STREBKOVA NA, et al. Comparative assessment of energy metabolism, body composition and metabolic features in children with hypothalamic and simple obesity. Obes Metab. 2020;17(3):249-256.
[33] GALI RAMAMOORTHY T, ALLEN TJ, DAVIES A, et al. Maternal overnutrition programs epigenetic changes in the regulatory regions of hypothalamic pomc in the offspring of rats. Int J Obes (Lond). 2018;42(8):1431-1444.
[34] KANG KS, YAHASHI S, MATSUDA K. Central and peripheral effects of ghrelin on energy balance, food intake and lipid metabolism in teleost fish. Peptides. 2011;32(11):2242-2247.
[35] VAN DEN TOP M, LYONS DJ, LEE K, et al. Pharmacological and molecular characterization of atp-sensitive k(+) conductances in cart and npy/agrp expressing neurons of the hypothalamic arcuate nucleus. Neuroscience. 2007;144(3):815-824.
[36] SHARMA A, JAYASENA CN, DHILLO WS. Regulation of the Hypothalamic-Pituitary-Testicular Axis: Pathophysiology of Hypogonadism. Endocrin Metab Clin. 2022;51(1):29-45.
[37] MICHLEWSKA MO. The contribution of astrocytes to obesity-associated metabolic disturbances. J Biomed Res. 2022;36(5):299-311.
[38] PAPAZOGLOU I, LEE JH, CUI ZZ, et al. A distinct hypothalamus-to-β cell circuit modulates insulin secretion. Cell Metab. 2022;34(2):285-98.
[39] ZHANG ZY, DODD GT, TIGANIS T. Protein tyrosine phosphatases in hypothalamic insulin and leptin signaling. Trends Pharmacol Sci. 2015; 36(10):661-674.
[40] ZHENG J, XIAO X, ZHANG Q, et al. Maternal and post-weaning high-fat, high-sucrose diet modulates glucose homeostasis and hypothalamic pomc promoter methylation in mouse offspring. Metab brain dis. 2015;30(5):1129-1137.