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Dyslipidemia, insulin resistance, and impairment of placental metabolism in the offspring of obese mothers

Published online by Cambridge University Press:  13 November 2020

Matthew Bucher ,
Kim Ramil C. Montaniel ,
Leslie Myatt ,
Susan Weintraub ,
Hagai Tavori  and
Alina Maloyan Open the ORCID record for Alina Maloyan [Opens in a new window]
Matthew Bucher
Affiliation:
Knight Cardiovascular Institute, School of Medicine, Oregon Health & Science University, Portland, OR, USA Department of OB/GYN, Oregon Health & Science University, Portland, OR, USA
Kim Ramil C. Montaniel
Affiliation:
Knight Cardiovascular Institute, School of Medicine, Oregon Health & Science University, Portland, OR, USA The Graduate Program in Biomedical Sciences (PBMS), Oregon Health & Science University, Portland, OR, USA
Leslie Myatt
Affiliation:
Department of OB/GYN, Oregon Health & Science University, Portland, OR, USA
Susan Weintraub
Affiliation:
Department of Biochemistry, The Metabolomics Core Facility, Institutional Mass Spectrometry Laboratory, University of Texas Health, San Antonio, TX, USA
Hagai Tavori
Affiliation:
Knight Cardiovascular Institute, School of Medicine, Oregon Health & Science University, Portland, OR, USA
Alina Maloyan*
Affiliation:
Knight Cardiovascular Institute, School of Medicine, Oregon Health & Science University, Portland, OR, USA The Graduate Program in Biomedical Sciences (PBMS), Oregon Health & Science University, Portland, OR, USA
*
Address for Correspondence: Alina Maloyan, Knight Cardiovascular Institute, School of Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, Oregon97239, USA. Email: [email protected]
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Abstract

Obesity is a chronic condition associated with dyslipidemia and insulin resistance. Here, we show that the offspring of obese mothers are dyslipidemic and insulin resistant from the outset.

Maternal and cord blood and placental tissues were collected following C-section at term. Patients were grouped as being normal weight (NW, BMI = 18–24.9) or obese (OB, BMI ≥ 30), and separated by fetal sex. We measured plasma lipids, insulin, and glucose in maternal and cord blood. Insulin resistance was quantified using the HOMA-IR. Placental markers of lipid and energy metabolism and relevant metabolites were measured by western blot and metabolomics, respectively.

For OB women, total cholesterol was decreased in both maternal and cord blood, while HDL was decreased only in cord blood, independent of sex. In babies born to OB women, cord blood insulin and insulin resistance were increased. Placental protein expression of the energy and lipid metabolism regulators PGC1α, and SIRT3, ERRα, CPT1α, and CPT2 decreased with maternal obesity in a sex-dependent manner (P < 0.05). Metabolomics showed lower levels of acylcarnitines C16:0, C18:2, and C20:4 in OB women’s placentas, suggesting a decrease in β-oxidation. Glutamine, glutamate, alpha-ketoglutarate (αKG), and 2-hydroxyglutarate (2-HG) were increased, and the glutamine-to-glutamate ratio decreased (P < 0.05), in OB placentas, suggesting induction of glutamate into αKG conversion to maintain a normal metabolic flux.

Newly-born offspring of obese mothers begin their lives dyslipidemic and insulin resistant. If not inherited genetically, such major metabolic perturbations might be explained by abnormal placental metabolism with potential long-term adverse consequences for the offspring’s health and wellbeing.

Keywords

Maternal obesitylipid profileplacental functionmetabolomicsinsulin resistance
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 12 , Issue 5 , October 2021 , pp. 738 - 747
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Copyright
© The Author(s), 2020. Published by Cambridge University Press in association with International Society for Developmental Origins of Health and Disease

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References

Hay, WW Jr Placental-fetal glucose exchange and fetal glucose metabolism. Trans Am Clin Climatol Assoc. 2006; 117, 321–340.Google ScholarPubMed
Sonagra, AD, Biradar, SM, Dattatreya, K, Murthy, DSJ. Normal pregnancy – a state of insulin resistance. J Clin Diagn Res. 2014; 8, CC01–CC3.Google Scholar
Homko, CJ, Sivan, E, Reece, EA, Boden, G. Fuel metabolism during pregnancy. Semin Reprod Endocrinol. 1999; 17, 119–125.CrossRefGoogle ScholarPubMed
Grieger, JA, Bianco-Miotto, T, Grzeskowiak, LE, et al. Metabolic syndrome in pregnancy and risk for adverse pregnancy outcomes: a prospective cohort of nulliparous women. PLoS Med. 2018; 15, e1002710.CrossRefGoogle ScholarPubMed
Carter, AM. Evolution of placental function in mammals: the molecular basis of gas and nutrient transfer, hormone secretion, and immune responses. Physiol Rev. 2012; 92, 1543–1576.CrossRefGoogle ScholarPubMed
Mele, J, Muralimanoharan, S, Maloyan, A, Myatt, L. Impaired mitochondrial function in human placenta with increased maternal adiposity. Am J Physiol Endocrinol Metab. 2014; 307, E419–E425.CrossRefGoogle ScholarPubMed
Challier, JC, Basu, S, Bintein, T, et al. Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. Placenta. 2008; 29, 274–281.CrossRefGoogle ScholarPubMed
Agarwal, P, Morriseau, TS, Kereliuk, SM, Doucette, CA, Wicklow, BA, Dolinsky, VW. Maternal obesity, diabetes during pregnancy and epigenetic mechanisms that influence the developmental origins of cardiometabolic disease in the offspring. Crit Rev Clin Lab Sci. 2018; 55, 71–101.CrossRefGoogle ScholarPubMed
Muralimanoharan, S, Gao, X, Weintraub, S, Myatt, L, Maloyan, A. Sexual dimorphism in activation of placental autophagy in obese women with evidence for fetal programming from a placenta-specific mouse model. Autophagy. 2016; 12, 752–769.CrossRefGoogle ScholarPubMed
Simon, B, Bucher, M, Maloyan, A. A primary human trophoblast model to study the effect of inflammation associated with maternal obesity on regulation of autophagy in the placenta. J vis Exp. 2017; 127, 56484.Google Scholar
Song, DK, Hong, YS, Sung, YA, Lee, H. Insulin resistance according to beta-cell function in women with polycystic ovary syndrome and normal glucose tolerance. PloS One. 2017; 12, e0178120.CrossRefGoogle ScholarPubMed
Minicocci, I, Santini, S, Cantisani, V, et al. Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis. J Lipid Res. 2013; 54, 3481–3490.CrossRefGoogle ScholarPubMed
Reaven, GM, Lerner, RL, Stern, MP, Farquhar, JW. Role of insulin in endogenous hypertriglyceridemia. J Clin Invest. 1967; 46, 1756–1767.CrossRefGoogle ScholarPubMed
Liu, HY, Yehuda-Shnaidman, E, Hong, T, et al. Prolonged exposure to insulin suppresses mitochondrial production in primary hepatocytes. J Biol Chem. 2009; 284, 14087–14095.CrossRefGoogle ScholarPubMed
Mei, S, Gu, H, Yang, X, Guo, H, Liu, Z, Cao, W. Prolonged exposure to insulin induces mitochondrion-derived oxidative stress through increasing mitochondrial cholesterol content in hepatocytes. Endocrinology. 2012; 153, 2120–2129.CrossRefGoogle ScholarPubMed
Lin, J, Handschin, C, Spiegelman, BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metabol. 2005; 1, 361–370.CrossRefGoogle ScholarPubMed
Li, X, Monks, B, Ge, Q, Birnbaum, MJ. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator. Nature. 2007; 447, 1012–1016.CrossRefGoogle ScholarPubMed
Casaburi, I, Chimento, A, De Luca, A, et al. Cholesterol as an endogenous ERRalpha agonist: a new perspective to cancer treatment. Front Endocrinol. 2018; 9, 525.CrossRefGoogle ScholarPubMed
Mirebeau-Prunier, D, Le Pennec, S, Jacques, C, et al. Estrogen-related receptor alpha and PGC-1-related coactivator constitute a novel complex mediating the biogenesis of functional mitochondria. FEBS J. 2010; 277, 713–725.CrossRefGoogle ScholarPubMed
Brenmoehl, J, Hoeflich, A. Dual control of mitochondrial biogenesis by sirtuin 1 and sirtuin 3. Mitochondrion. 2013; 13, 755–761.CrossRefGoogle ScholarPubMed
Schooneman, MG, Vaz, FM, Houten, SM, Soeters, MR. Acylcarnitines: reflecting or inflicting insulin resistance? Diabetes. 2013; 62, 1–8.CrossRefGoogle ScholarPubMed
Goodpaster, BH, Sparks, LM. Metabolic flexibility in health and disease. Cell Metabol. 2017; 25, 1027–1036.CrossRefGoogle ScholarPubMed
Saini-Chohan, HK, Mitchell, RW, Vaz, FM, Zelinski, T, Hatch, GM. Delineating the role of alterations in lipid metabolism to the pathogenesis of inherited skeletal and cardiac muscle disorders: thematic review series: genetics of human lipid diseases. J Lipid Res. 2012; 53, 4–27.CrossRefGoogle ScholarPubMed
Dang, CV. Links between metabolism and cancer. Genes Develop. 2012; 26, 877–890.CrossRefGoogle ScholarPubMed
Pearce, EJ, Pearce, EL. Immunometabolism in 2017: driving immunity: all roads lead to metabolism. Nat Rev Immunol. 2018; 18, 81–82.Google Scholar
de Luca, C, Olefsky, JM. Inflammation and insulin resistance. FEBS Lett. 2008; 582: 97–105.CrossRefGoogle ScholarPubMed
Martins, AR, Nachbar, RT, Gorjao, R, et al. Mechanisms underlying skeletal muscle insulin resistance induced by fatty acids: importance of the mitochondrial function. Lipids Health Dis. 2012; 11, 30.CrossRefGoogle ScholarPubMed
Karaderi, T, Drong, AW, Lindgren, CM. Insights into the genetic susceptibility to type 2 diabetes from genome-wide association studies of obesity-related traits. Curr Diab Rep. 2015; 15, 83.CrossRefGoogle ScholarPubMed
Di Meo, S, Iossa, S, Venditti, P. Skeletal muscle insulin resistance: role of mitochondria and other ROS sources. J Endocrinol. 2017; 233, R15–R42.CrossRefGoogle ScholarPubMed
Fernandez-Twinn, DS, Gascoin, G, Musial, B, et al. Exercise rescues obese mothers’ insulin sensitivity, placental hypoxia and male offspring insulin sensitivity. Sci Rep. 2017; 7, 44650.CrossRefGoogle ScholarPubMed
Maric, T, Kanu, C, Johnson, MR, Savvidou, MD. Maternal, neonatal insulin resistance and neonatal anthropometrics in pregnancies following bariatric surgery. Metabolism. 2019; 97, 25–31.Google Scholar
Tinius, RA, Cahill, AG, Strand, EA, Cade, WT. Altered maternal lipid metabolism is associated with higher inflammation in obese women during late pregnancy. Integr Obes Diabetes. 2015; 2, 168–175.Google ScholarPubMed
Lassance, L, Haghiac, M, Leahy, P, et al. Identification of early transcriptome signatures in placenta exposed to insulin and obesity. Am J Obstetr Gynecol. 2015; 212, 647.e1–647.11.CrossRefGoogle ScholarPubMed
Lassance, L, Haghiac, M, Minium, J, Catalano, P, Hauguel-de Mouzon, S. Obesity-induced down-regulation of the mitochondrial translocator protein (TSPO) impairs placental steroid production. J Clin Endocrinol Metabol. 2015; 100, E11–E18.CrossRefGoogle ScholarPubMed
Kim, JA, Wei, Y, Sowers, JR. Role of mitochondrial dysfunction in insulin resistance. Circ Res. 2008; 102, 401–414.CrossRefGoogle ScholarPubMed
Kelly, AC, Powell, TL, Jansson, T. Placental function in maternal obesity. Clin Sci. 2020; 134, 961–984.CrossRefGoogle ScholarPubMed
Javed, K, Fairweather, SJ. Amino acid transporters in the regulation of insulin secretion and signalling. Biochem Soc Trans. 2019; 47, 571–590.CrossRefGoogle ScholarPubMed
Segovia, SA, Vickers, MH, Gray, C, Reynolds, CM. Maternal obesity, inflammation, and developmental programming. BioMed Res Int. 2014; 2014, 418975.CrossRefGoogle ScholarPubMed
Feingold, KR. Obesity and dyslipidemia. In Endotext (eds. Feingold, KR, Anawalt, B, Boyce, A, et al.), 2000. MDText.com, Inc., South Dartmouth, MA.Google Scholar
Geraghty, AA, Alberdi, G, O’Sullivan, EJ, et al. Maternal and fetal blood lipid concentrations during pregnancy differ by maternal body mass index: findings from the ROLO study. BMC Pregnancy Childbirth. 2017; 17, 360.CrossRefGoogle ScholarPubMed
Woollett, L, Heubi, JE. Fetal and neonatal cholesterol metabolism. In Endotext (eds. Feingold KR, Anawalt B, Boyce A, et al.), 2000. MDText.com, Inc., South Dartmouth, MA.Google ScholarPubMed
Woollett, LA. Fetal lipid metabolism. Front Biosci. 2001; 6, D536–D545.CrossRefGoogle ScholarPubMed
Vahratian, A, Misra, VK, Trudeau, S, Misra, DP. Prepregnancy body mass index and gestational age-dependent changes in lipid levels during pregnancy. Obstetr Gynecol. 2010; 116, 107–113.CrossRefGoogle ScholarPubMed
Meyer, BJ, Stewart, FM, Brown, EA, et al. Maternal obesity is associated with the formation of small dense LDL and hypoadiponectinemia in the third trimester. J Clin Endocrinol Metab. 2013; 98, 643–652.CrossRefGoogle ScholarPubMed
Augsten, M, Hackl, H, Ebner, B, et al. Fetal HDL/apoE: a novel regulator of gene expression in human placental endothelial cells. Physiol Genomics. 2011; 43, 1255–1262.CrossRefGoogle ScholarPubMed
Ethier-Chiasson, M, Duchesne, A, Forest, JC, et al. Influence of maternal lipid profile on placental protein expression of LDLr and SR-BI. Biochem Biophys Res Commun. 2007; 359, 8–14.CrossRefGoogle ScholarPubMed
Zhang, Y, Ma, KL, Ruan, XZ, Liu, BC. Dysregulation of the low-density lipoprotein receptor pathway is involved in lipid disorder-mediated organ injury. Int J Biol Sci. 2016; 12, 569–579.CrossRefGoogle ScholarPubMed
Rust, S, Rosier, M, Funke, H, et al. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet. 1999; 22, 352–355.CrossRefGoogle ScholarPubMed
Brooks-Wilson, A, Marcil, M, Clee, SM, et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet. 1999; 22, 336–345.CrossRefGoogle ScholarPubMed
Blackmore, HL, Ozanne, SE. Maternal diet-induced obesity and offspring cardiovascular health. J Dev Orig Health Dis. 2013; 4, 338–347.CrossRefGoogle ScholarPubMed
Petersen, KF, Dufour, S, Befroy, D, Garcia, R, Shulman, GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med. 2004; 350, 664–671.CrossRefGoogle ScholarPubMed
Serra, D, Mera, P, Malandrino, MI, Mir, JF, Herrero, L. Mitochondrial fatty acid oxidation in obesity. Antioxid Redox Signal. 2013; 19, 269–284.CrossRefGoogle ScholarPubMed
Seiler, SE, Martin, OJ, Noland, RC, et al. Obesity and lipid stress inhibit carnitine acetyltransferase activity. J Lipid Res. 2014; 55, 635–644.CrossRefGoogle ScholarPubMed
Noland, RC, Koves, TR, Seiler, SE, et al. Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control. J Biol Chem. 2009; 284, 22840–22852.CrossRefGoogle ScholarPubMed
Becker, C, Kukat, A, Szczepanowska, K, et al. CLPP deficiency protects against metabolic syndrome but hinders adaptive thermogenesis. EMBO Rep. 2018; 19.Google ScholarPubMed
Hulver, MW, Berggren, JR, Cortright, RN, et al. Skeletal muscle lipid metabolism with obesity. Am J Physiol Endocrinol Metab. 2003; 284, E741–E747.CrossRefGoogle ScholarPubMed
Fujiwara, N, Nakagawa, H, Enooku, K, et al. CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity. Gut. 2018; 67, 1493–1504.CrossRefGoogle ScholarPubMed
Hastie, R, Lappas, M. The effect of pre-existing maternal obesity and diabetes on placental mitochondrial content and electron transport chain activity. Placenta. 2014; 35, 673–683.CrossRefGoogle ScholarPubMed
St-Pierre, J, Drori, S, Uldry, M, et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006; 127, 397–408.CrossRefGoogle ScholarPubMed
Arany, Z, Foo, SY, Ma, Y, et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature. 2008; 451, 1008–1012.CrossRefGoogle ScholarPubMed
Crunkhorn, S, Dearie, F, Mantzoros, C, et al. Peroxisome proliferator activator receptor gamma coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation. J Biol Chem. 2007; 282, 15439–15450.CrossRefGoogle ScholarPubMed
Supruniuk, E, Mikłosz, A, Chabowski, A. The implication of PGC-1α on fatty acid transport across plasma and mitochondrial membranes in the insulin sensitive tissues. Front Physiol. 2017; 8, 923.Google Scholar
Bause, AS, Haigis, MC. SIRT3 regulation of mitochondrial oxidative stress. Exp Gerontol. 2013; 48, 634–639.CrossRefGoogle ScholarPubMed
Ansari, A, Rahman, MS, Saha, SK, Saikot, FK, Deep, A, Kim, KH. Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease. Aging Cell. 2017; 16, 4–16.CrossRefGoogle ScholarPubMed
Ranhotra, HS. Estrogen-related receptor alpha and mitochondria: tale of the titans. J Recept Signal Transduct Res. 2015; 35, 386–390.CrossRefGoogle ScholarPubMed
Mootha, VK, Handschin, C, Arlow, D, et al. Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci U S A. 2004; 101, 6570–6575.CrossRefGoogle ScholarPubMed
Qu, Q, Zeng, F, Liu, X, Wang, QJ, Deng, F. Fatty acid oxidation and carnitine palmitoyltransferase I: emerging therapeutic targets in cancer. Cell Death Dis. 2016; 7, e2226.CrossRefGoogle ScholarPubMed
Kim, JY, Hickner, RC, Cortright, RL, Dohm, GL, Houmard, JA. Lipid oxidation is reduced in obese human skeletal muscle. Am J Physiol Endocrinol Metab. 2000; 279, E1039–E1044.CrossRefGoogle ScholarPubMed
Watford, M. Glutamine and glutamate: nonessential or essential amino acids? Anim Nutr. 2015; 1, 119–122.CrossRefGoogle ScholarPubMed
Isganaitis, E, Rifas-Shiman, SL, Oken, E, et al. Associations of cord blood metabolites with early childhood obesity risk. Int J Obes. 2015; 39, 1041–1048.CrossRefGoogle ScholarPubMed
Cheng, S, Rhee, EP, Larson, MG, et al. Metabolite profiling identifies pathways associated with metabolic risk in humans. Circulation. 2012; 125, 2222–2231.CrossRefGoogle ScholarPubMed
Rasmussen, KM, Catalano, PM, Yaktine, AL. New guidelines for weight gain during pregnancy: what obstetrician/gynecologists should know. Curr Opin Obstet Gynecol. 2009; 21, 521–526.CrossRefGoogle ScholarPubMed
Starling, AP, Brinton, JT, Glueck, DH, et al. Associations of maternal BMI and gestational weight gain with neonatal adiposity in the Healthy Start study. Am J Clin Nutr. 2015; 101, 302–309.CrossRefGoogle ScholarPubMed
Siega-Riz, AM, Viswanathan, M, Moos, MK, et al. A systematic review of outcomes of maternal weight gain according to the Institute of Medicine recommendations: birthweight, fetal growth, and postpartum weight retention. Am J Obstetr Gynecol. 2009; 201, 339.e1–339.e14.CrossRefGoogle ScholarPubMed
Marshall, NE, Guild, C, Cheng, YW, Caughey, AB, Halloran, DR. Maternal superobesity and perinatal outcomes. Am J Obstetr Gynecol. 2012; 206, 417.e1–417.e6.CrossRefGoogle ScholarPubMed
Catalano, PM, Mele, L, Landon, MB, et al. Inadequate weight gain in overweight and obese pregnant women: what is the effect on fetal growth? Am J Obstetr Gynecol. 2014; 211, 137.e1–137.e7.CrossRefGoogle ScholarPubMed
Leon-Garcia, SM, Roeder, HA, Nelson, KK, et al. Maternal obesity and sex-specific differences in placental pathology. Placenta. 2016; 38, 33–40.CrossRefGoogle ScholarPubMed
Muralimanoharan, S, Guo, C, Myatt, L, Maloyan, A. Sexual dimorphism in miR-210 expression and mitochondrial dysfunction in the placenta with maternal obesity. Int J Obesity. 2015; 39, 1274–1281.CrossRefGoogle ScholarPubMed
Rosenfeld, CS. Sex-specific placental responses in fetal development. Endocrinology. 2015; 156, 3422–3434.CrossRefGoogle ScholarPubMed
Mando, C, Calabrese, S, Mazzocco, MI, et al. Sex specific adaptations in placental biometry of overweight and obese women. Placenta. 2016; 38, 1–7.CrossRefGoogle ScholarPubMed
Aye, IL, Lager, S, Ramirez, VI, et al. Increasing maternal body mass index is associated with systemic inflammation in the mother and the activation of distinct placental inflammatory pathways. Biol Reprod. 2014; 90, 129.CrossRefGoogle ScholarPubMed
Houde, AA, St-Pierre, J, Hivert, MF, et al. Placental lipoprotein lipase DNA methylation levels are associated with gestational diabetes mellitus and maternal and cord blood lipid profiles. J Dev Orig Health Dis. 2014; 5, 132–141.CrossRefGoogle ScholarPubMed
Houde, AA, Guay, SP, Desgagne, V, et al. Adaptations of placental and cord blood ABCA1 DNA methylation profile to maternal metabolic status. Epigenetics. 2013; 8, 1289–1302.CrossRefGoogle ScholarPubMed
Lesseur, C, Armstrong, DA, Paquette, AG, Li, Z, Padbury, JF, Marsit, CJ. Maternal obesity and gestational diabetes are associated with placental leptin DNA methylation. Am J Obstetr Gynecol. 2014; 211, 654.e1–654.e9.CrossRefGoogle ScholarPubMed
Barcena de Arellano, ML, Pozdniakova, S, Kuhl, AA, Baczko, I, Ladilov, Y, Regitz-Zagrosek, V. Sex differences in the aging human heart: decreased sirtuins, pro-inflammatory shift and reduced anti-oxidative defense. Aging. 2019; 11, 1918–1933.CrossRefGoogle ScholarPubMed
Lejri, I, Grimm, A, Eckert, A. Mitochondria, Estrogen and female brain aging. Front Aging Neurosci. 2018; 10, 124.CrossRefGoogle ScholarPubMed
Morselli, E, Criollo, A, Rodriguez-Navas, C, Clegg, DJ. Chronic high fat diet consumption impairs metabolic health of male mice. Inflamm Cell Signal. 2014; 1, e561.Google ScholarPubMed
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