Journal of Food and Nutrition Research
ISSN (Print): 2333-1119 ISSN (Online): 2333-1240 Website: Editor-in-chief: Prabhat Kumar Mandal
Open Access
Journal Browser
Journal of Food and Nutrition Research. 2019, 7(2), 96-104
DOI: 10.12691/jfnr-7-2-1
Open AccessArticle

Methionine Restriction Diet Improves Metabolic Function in Obese C57BL/6 Female Mice via AMPK/SIRT1/PGC1α Pathway

Seba Harphoush1, 2, Guoqing Wu1, 3, Margaret Zaitoun1, 2, Yonghui Shi1, 3 and Guowei Le1, 3,

1State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, PR China

2Faculty of Health Science, Al-baath University, Homs, Syria;School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, PR China

3School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, PR China

Pub. Date: February 03, 2019

Cite this paper:
Seba Harphoush, Guoqing Wu, Margaret Zaitoun, Yonghui Shi and Guowei Le. Methionine Restriction Diet Improves Metabolic Function in Obese C57BL/6 Female Mice via AMPK/SIRT1/PGC1α Pathway. Journal of Food and Nutrition Research. 2019; 7(2):96-104. doi: 10.12691/jfnr-7-2-1


Methionine restriction has been proven to reverse age and obesity related metabolic diseases. Basically, MR regulates energy homeostasis in the whole body contributing to enhanced insulin sensitivity and improved redox status. There is no studies until now that comprehensively focus on the impact of MR on reproduction performance. The aim of this work was to investigate the reproductive system response of female obese model toward MR and clarify the possible mechanism. Females C57BL/6 were subjected to control diet (CON, 0.86% methionine + 4% fat), High Fat Diet (HFD, 0.86% methionine + 20% fat), High fat methionine Restricted diet (MR, 0.17% methionine + 20% fat). HFD showed impaired reproduction performance characteristic by impaired conception ability and lactation difficulties. MR improved oxidative stress, metabolic parameters, mammary and ovarian morphology. MR enhanced ovulation, lactation, and especially regulated metabolism efficiency via AMPK/SIRT1/PGC1. This study is the first to suggest that MR can ameliorate reproductive disorders induced by obesity.

methionine restriction high fat diet obesity reproduction metabolic dysfunction

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit


[1]  Broughton, D.E. and K.H. Moley, Obesity and female infertility: potential mediators of obesity's impact. Fertil Steril, 2017. 107(4): p. 840-847.
[2]  He, Y., et al., Association of childhood obesity with female infertility in adulthood: a 25-year follow-up study. Fertil Steril, 2018. 110(4): p. 596-604 e1.
[3]  Moslehi, N., et al., Is ovarian reserve associated with body mass index and obesity in reproductive aged women? A meta-analysis. Menopause, 2018. 25(9): p. 1046-1055.
[4]  Gesink Law, D., R.F. Maclehose, and M.P. Longnecker, Obesity and time to pregnancy. Human Reproduction, 2006. 22(2): p. 414-420.
[5]  Rasmussen, K.M., J.A. Hilson, and C.L. Kjolhede, Obesity may impair lactogenesis II. The Journal of nutrition, 2001. 131(11): p. 3009S-3011S.
[6]  Amir, L.H. and S. Donath, A systematic review of maternal obesity and breastfeeding intention, initiation and duration. BMC pregnancy and childbirth, 2007. 7(1): p. 9.
[7]  Legro, R.S., Effects of obesity treatment on female reproduction: results do not match expectations. Fertil Steril, 2017. 107(4): p. 860-867.
[8]  Stang, J. and L.G. Huffman, Position of the Academy of Nutrition and Dietetics: Obesity, Reproduction, and Pregnancy Outcomes. J Acad Nutr Diet, 2016. 116(4): p. 677- 91.
[9]  Malloy, V.L., et al., Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction. Aging cell, 2006. 5(4): p. 305-314.
[10]  Stone, K.P., et al., Mechanisms of increased in vivo insulin sensitivity by dietary methionine restriction in mice. Diabetes, 2014: p. DB_140464.
[11]  Hasek, B.E., et al., Dietary methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted states. Am J Physiol Regul Integr Comp Physiol, 2010. 299(3): p. R728-39.
[12]  Yang, Y., et al., Dietary methionine restriction reduces hepatic steatosis and oxidative stress in high-fat-fed mice by promoting H2S production. Food Funct, 2018.
[13]  Yang, Y., et al., Dietary methionine restriction regulated energy and protein homeostasis by improving thyroid function in high fat diet mice. Food Funct, 2018. 9(7): p. 3718-3731.
[14]  Kalhan, S.C. and S.E. Marczewski, Methionine, homocysteine, one carbon metabolism and fetal growth. Reviews in Endocrine and Metabolic Disorders, 2012. 13(2): p. 109-119.
[15]  Rees, W.D., F.A. Wilson, and C.A. Maloney, Sulfur amino acid metabolism in pregnancy: the impact of methionine in the maternal diet. The Journal of nutrition, 2006. 136(6): p. 1701S-1705S.
[16]  Kamikawa, A., et al., Diet‐induced obesity disrupts ductal development in the mammary glands of nonpregnant mice. Developmental dynamics: an official publication of the American Association of Anatomists, 2009. 238(5): p. 1092-1099.
[17]  Flint, D.J., et al., Diet-induced obesity impairs mammary development and lactogenesis in murine mammary gland. American Journal of Physiology-Endocrinology and Metabolism, 2005. 288(6): p. E1179-E1187.
[18]  Xu, M., et al., Effect of high fat dietary intake during maternal gestation on offspring ovarian health in a pig model. Nutrients, 2016. 8(8): p. 498.
[19]  Sohrabi, M., et al., Effect of a high fat diet on ovary morphology, in vitro development, in vitro fertilisation rate and oocyte quality in mice. Singapore medical journal, 2015. 56(10): p. 573.
[20]  Wu, Y., et al., High fat diet triggers cell cycle arrest and excessive apoptosis of granulosa cells during the follicular development. Biochemical and biophysical research communications, 2015. 466(3): p. 599-605.
[21]  Wang, N., et al., Obesity accelerates ovarian follicle development and follicle loss in rats. Metabolism, 2014. 63(1): p. 94-103.
[22]  Plante, I., M.K. Stewart, and D.W. Laird, Evaluation of mammary gland development and function in mouse models. Journal of visualized experiments: JoVE, 2011(53).
[23]  McGinley, J.N. and H.J. Thompson, Quantitative assessment of mammary gland density in rodents using digital image analysis. Biological procedures online, 2011. 13(1): p. 4.
[24]  Wanders, D., et al., The Components of Age-Dependent Effects of Dietary Methionine Restriction on Energy Balance in Rats. Obesity (Silver Spring), 2018. 26(4): p. 740-746.
[25]  Mowry, A.V., et al., Mitochondrial function and bioenergetic trade‐offs during lactation in the house mouse (Mus musculus). Ecology and evolution, 2017. 7(9): p. 2994-3005.
[26]  Stone, K.P., et al., Mechanisms of increased in vivo insulin sensitivity by dietary methionine restriction in mice. Diabetes, 2014. 63(11): p. 3721-33.
[27]  Latimer, M.N., B.M. Cleveland, and P.R. Biga, Dietary methionine restriction: Effects on glucose tolerance, lipid content and micro-RNA composition in the muscle of rainbow trout. Comp Biochem Physiol C Toxicol Pharmacol, 2018. 208: p. 47-52.
[28]  Ying, Z., et al., Effects of dietary methionine restriction on postnatal growth, insulin sensitivity, and glucose metabolism in intrauterine growth retardation pigs at 49 and 105 days of age. J Anim Sci, 2018.
[29]  Lees, E.K., et al., Direct comparison of methionine restriction with leucine restriction on the metabolic health of C57BL/6J mice. Sci Rep, 2017. 7(1): p. 9977.
[30]  Yin, J., et al., Metabolic Regulation of Methionine Restriction in Diabetes. Mol Nutr Food Res, 2018. 62(10): p. e1700951.
[31]  Liu, G., et al., Methionine restriction on oxidative stress and immune response in dss-induced colitis mice. Oncotarget, 2017. 8(27): p. 44511-44520.
[32]  Caro, P., et al., Forty percent and eighty percent methionine restriction decrease mitochondrial ROS generation and oxidative stress in rat liver. Biogerontology, 2008. 9(3): p. 183-96.
[33]  Nteeba, J., et al., Progressive obesity alters ovarian insulin, phosphatidylinositol-3 kinase, and chemical metabolism signaling pathways and potentiates ovotoxicity induced by phosphoramide mustard in mice. Biol Reprod, 2017. 96(2): p. 478-490.
[34]  Barcena, C., et al., Methionine Restriction Extends Lifespan in Progeroid Mice and Alters Lipid and Bile Acid Metabolism. Cell Rep, 2018. 24(9): p. 2392-2403.
[35]  Brown-Borg, H.M., Reduced growth hormone signaling and methionine restriction: interventions that improve metabolic health and extend life span. Ann N Y Acad Sci, 2016. 1363: p.40-9.
[36]  Perrone, C.E., et al., Methionine restriction effects on mitochondrial biogenesis and aerobic capacity in white adipose tissue, liver, and skeletal muscle of F344 rats. Metabolism, 2010. 59(7): p. 1000-11.
[37]  Zhang, H.-H., et al., SIRT1 attenuates high glucose-induced insulin resistance via reducing mitochondrial dysfunction in skeletal muscle cells. Experimental Biology and Medicine, 2015. 240(5): p. 557-565.
[38]  Zhou, X.-L., et al., SIRT1 activator (SRT1720) improves the follicle reserve and prolongs the ovarian lifespan of diet-induced obesity in female mice via activating SIRT1 and suppressing mTOR signaling. Journal of ovarian research, 2014. 7(1): p. 97.
[39]  Langin, D., The role of uncoupling protein 2 in the development of type 2 diabetes. Drugs Today (Barc), 2003. 39(4): p. 287-295.
[40]  Yonezawa, T., et al., Regulation of uncoupling protein 2 expression by long-chain fatty acids and hormones in bovine mammary epithelial cells. Biochemical and biophysical research communications, 2008. 375(2): p. 280-285.
[41]  Ge, H., et al., Effects of mitochondrial uncoupling protein 2 inhibition by genipin in human cumulus cells. BioMed research international, 2015. 2015.