Leptin in reproduction and hypertension in pregnancy
Harbindarjeet Singh A * , Fayez A. Almabhouh A B , Hisham S. Ibrahim Alshaikhli C , Maryam Jameelah Md Hassan A , Suzanna Daud A , Rosfayati Othman D and Muhd Fakh Rur Razi Md Salleh DA
B
C
D
Abstract
Leptin has important roles in numerous physiological functions, including those in the regulation of energy balance, and in immune and reproductive systems. However, in the recent years, evidence has implicated it in a number of obesity-related diseases, where its concentrations in serum are significantly elevated. Elevated serum leptin concentrations and increased placental leptin secretion have been reported in women with hypertensive disorders of pregnancy. Whether leptin is responsible for this disorder remains to be established. Leptin injections in healthy rats and mice during pregnancy result in endothelial activation, increased blood pressure and proteinuria. A potential role for leptin in the pathogenesis of pre-eclampsia is hypothesised, particularly in women who are overweight or obese where serum leptin concentrations are often elevated. This review summarises pertinent information in the literature on the role of leptin in puberty, pregnancy, and hypertensive disorders of pregnancy. In particular, the possible mechanism that may be involved in leptin-induced increase in blood pressure and proteinuria during pregnancy and the potential role of marinobufagenin in this disease entity. We hypothesise a significant role for oxidative stress in this, and propose a conceptual framework on the events that lead to endothelial activation, raised blood pressure and proteinuria following leptin administration.
Keywords: ACE2, blood pressure, leptin, marinobufagenin, pre-eclampsia, pregnancy, proteinuria, puberty.
References
Abraham T, Romani AMP (2022) The relationship between obesity and pre-eclampsia: incidental risks and identification of potential biomarkers for pre-eclampsia. Cells 11(9), 1548.
| Crossref | Google Scholar | PubMed |
Adair D, Buckalew V, Taylor K, Ernest JM, Frye AH, Evans C, Veille J-C (1996) Elevated endoxin-like factor complicating a multifetal second trimester pregnancy: treatment with digoxin-binding immunoglobulin. American Journal of Nephrology 16(6), 529-531.
| Crossref | Google Scholar | PubMed |
Adair CD, Luper A, Rose JC, Russell G, Veille J-C, Buckalew VM (2009) The hemodynamic effects of intravenous digoxin-binding fab immunoglobulin in severe preeclampsia: a double-blind, randomized, clinical trial. Journal of Perinatology 29(4), 284-289.
| Crossref | Google Scholar | PubMed |
Agalakova NI, Kolodkin NI, Adair CD, Trashkov AP, Bagrov AY (2021) Preeclampsia: cardiotonic steroids, fibrosis, fli1 and hint to carcinogenesis. International Journal of Molecular Sciences 22(4), 1941.
| Crossref | Google Scholar | PubMed |
Ahima RS, Dushay J, Flier SN, Prabakaran D, Flier JS (1997) Leptin accelerates the onset of puberty in normal female mice. Journal of Clinical Investigation 99(3), 391-395.
| Crossref | Google Scholar | PubMed |
Akhter N, CarlLee T, Syed MM, Odle AK, Cozart MA, Haney AC, Allensworth-James ML, Beneš H, Childs GV (2014) Selective deletion of leptin receptors in gonadotropes reveals activin and GnRH-binding sites as leptin targets in support of fertility. Endocrinology 155(10), 4027-4042.
| Crossref | Google Scholar | PubMed |
Al-Atawi FS, Addar MH, Warsy AS, Babay ZA (2004) Leptin concentration during different trimesters of pregnancy and its relation to other pregnancy hormones. Saudi Medical Journal 25(11), 1617-1622.
| Google Scholar | PubMed |
Almabhouh FA, Singh HJ (2023) The impact of leptin on sperm. Reproduction, Fertility and Development 35(8), 459-468.
| Crossref | Google Scholar | PubMed |
Almabhouh FA, Osman K, Siti Fatimah I, Sergey G, Gnanou J, Singh HJ (2015) Effects of leptin on sperm count and morphology in Sprague–Dawley rats and their reversibility following a 6-week recovery period. Andrologia 47(7), 751-758.
| Crossref | Google Scholar | PubMed |
Almabhouh FA, Osman K, Ibrahim SF, Gupalo S, Gnanou J, Ibrahim E, Singh HJ (2017) Melatonin ameliorates the adverse effects of leptin on sperm. Asian Journal of Andrology 19(6), 647-654.
| Crossref | Google Scholar | PubMed |
Almabhouh F, Abdul Aziz NAA, Durairajanayagam D, Singh HJ (2020) Could leptin be responsible for the reproductive dysfunction in obese men? Reproductive Biology 20(1), 106-110.
| Crossref | Google Scholar |
Anim-Nyame N, Sooranna SR, Steer PJ, Johnson MR (2000) Longitudinal analysis of maternal plasma leptin concentrations during normal pregnancy and pre-eclampsia. Human Reproduction 15, 2033-2036.
| Crossref | Google Scholar | PubMed |
Aragno M, Mastrocola R, Alloatti G, Vercellinatto I, Bardini P, Geuna S, Catalano MG, Danni O, Boccuzzi G (2008) Oxidative stress triggers cardiac fibrosis in the heart of diabetic rats. Endocrinology 149(1), 380-388.
| Crossref | Google Scholar |
Ashworth CJ, Hoggard N, Thomas L, Mercer JG, Wallace JM, Lea RG (2000) Placental leptin. Reviews of Reproduction 5, 18-24.
| Crossref | Google Scholar | PubMed |
Avraham Y, Dayan M, Lassri V, Vorobiev L, Davidi N, Chernoguz D, Berry E, Leker RR (2013) Delayed leptin administration after stroke induces neurogenesis and angiogenesis. Journal of Neuroscience Research 91(2), 187-195.
| Crossref | Google Scholar | PubMed |
Bagrov AY, Shapiro JI, Fedorova OV (2009) Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets. Pharmacological Reviews 61(1), 9-38.
| Crossref | Google Scholar | PubMed |
Baker ER (1985) Body weight and the initiation of puberty. Clinical Obstetrics and Gynecology 28(3), 573-579.
| Crossref | Google Scholar | PubMed |
Batt RAL, Everard DM, Gillies G, Wilkinson M, Wilson CA, Yeo TA (1982) Investigation into the hypogonadism of the obese mouse (genotype ob/ob). Reproduction 64(2), 363-371.
| Crossref | Google Scholar | PubMed |
Bełtowski J, Wójcicka G, Jamroz-Wiśniewska A (2006) Role of nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) in the regulation of blood pressure by leptin in lean and obese rats. Life Sciences 79(1), 63-71.
| Crossref | Google Scholar | PubMed |
Bharadwaj MS, Strawn WB, Groban L, Yamaleyeva LM, Chappell MC, Horta C, Atkins K, Firmes L, Gurley SB, Brosnihan KB (2011) Angiotensin-Converting enzyme 2 deficiency is associated with impaired gestational weight gain and fetal growth restriction. Hypertension 58(5), 852-858.
| Crossref | Google Scholar | PubMed |
Boden G, Chen X, Mozzoli M, Ryan I (1996) Effect of fasting on serum leptin in normal human subjects. The Journal of Clinical Endocrinology & Metabolism 81(9), 3419-23.
| Crossref | Google Scholar | PubMed |
Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ (2008) Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. American Journal of Kidney Diseases 51(2), 199-211.
| Crossref | Google Scholar | PubMed |
Brunton PJ, Russell JA, Hirst JJ (2014) Allopregnanolone in the brain: protecting pregnancy and birth outcomes. Progress in Neurobiology 113, 106-136.
| Crossref | Google Scholar |
Cao R, Brakenhielm E, Wahlestedt C, Thyberg J, Cao Y (2001) Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proceedings of the National Academy of Sciences United States of America 98(11), 6390-6395.
| Crossref | Google Scholar | PubMed |
Carullo N, Fabiano G, D’Agostino M, Zicarelli MT, Musolino M, Presta P, Michael A, Andreucci M, Bolignano D, Coppolino G (2023) New insights on the role of marinobufagenin from bench to bedside in cardiovascular and kidney diseases. International Journal of Molecular Sciences 24(13), 11186.
| Crossref | Google Scholar | PubMed |
Chehab FF, Lim ME, Lu R (1996) Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nature Genetics 12(3), 318-320.
| Crossref | Google Scholar | PubMed |
Cheresh P, Kim S-J, Tulasiram S, Kamp DW (2013) Oxidative stress and pulmonary fibrosis. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease 1832(7), 1028-1040.
| Crossref | Google Scholar | PubMed |
Cheung CC, Thornton JE, Nurani SD, Clifton DK, Steiner RA (2001) A reassessment of leptin’s role in triggering the onset of puberty in the rat and mouse. Neuroendocrinology 74(1), 12-21.
| Crossref | Google Scholar | PubMed |
Chiarello DI, Abad C, Rojas D, Toledo F, Vázquez CM, Mate A, Sobrevia L, Marín R (2020) Oxidative stress: normal pregnancy versus preeclampsia. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease 1866(2), 165354.
| Crossref | Google Scholar | PubMed |
Coppolino G, Leonardi G, Andreucci M, Bolignano D (2018) Oxidative stress and kidney function: a brief update. Current Pharmaceutical Design 24(40), 4794-4799.
| Crossref | Google Scholar | PubMed |
Crane C, Akhter N, Johnson BW, Iruthayanathan M, Syed F, Kudo A, Zhou Y-H, Childs GV (2007) Fasting and glucose effects on pituitary leptin expression: is leptin a local signal for nutrient status? Journal of Histochemistry & Cytochemistry 55(10), 1059-1073.
| Crossref | Google Scholar | PubMed |
De Biasi SN, Apfelbaum LI, Apfelbaum ME (2001) In vitro effect of leptin on LH release by anterior pituitary glands from female rats at the time of spontaneous and steroid-induced LH surge. European Journal of Endocrinology 145(5), 659-665.
| Crossref | Google Scholar | PubMed |
de Heredia FP, Gómez-Martínez S, Marcos A (2012) Obesity, inflammation and the immune system. Proceedings of the Nutrition Society 71(2), 332-338.
| Crossref | Google Scholar | PubMed |
de Knegt VE, Hedley PL, Kanters JK, Thagaard IN, Krebs L, Christiansen M, Lausten-Thomsen U (2021) The role of leptin in fetal growth during pre-eclampsia. International Journal of Molecular Sciences 22(9), 4569.
| Crossref | Google Scholar |
Donato J, Jr, Elias CF (2011) The ventral premammillary nucleus links metabolic cues and reproduction. Frontiers in Endocrinology 2, 57.
| Crossref | Google Scholar |
Doster Y, Demir BC, Atalay MA, Durusoy EE, Kucukkomurcu S (2016) The possible role of serum leptin in preeclampsia. Clinical and Experimental Obstetrics & Gynecology 43(1), 98-102.
| Crossref | Google Scholar | PubMed |
Elias CF, Purohit D (2013) Leptin signaling and circuits in puberty and fertility. Cellular and Molecular Life Sciences 70(5), 841-862.
| Crossref | Google Scholar | PubMed |
El Shahat AM, Ahmed AB, Ahmed MR, Mohamed HS (2013) Maternal serum leptin as a marker of preeclampsia. Archives of Gynecology and Obstetrics 288(6), 1317-1322.
| Crossref | Google Scholar | PubMed |
Faulkner JL, Wright D, Antonova G, Jaffe IZ, Kennard S, Belin de Chantemèle EJ (2022) Midgestation leptin infusion induces characteristics of clinical preeclampsia in mice, which is ablated by endothelial mineralocorticoid receptor deletion. Hypertension 79(7), 1536-1547.
| Crossref | Google Scholar | PubMed |
Fedorova OV, Kolodkin NI, Agalakova NI, Namikas AR, Bzhelyansky A, St-Louis J, Lakatta EG, Bagrov AY (2005) Antibody to marinobufagenin lowers blood pressure in pregnant rats on a high NaCl intake. Journal of Hypertension 23(4), 835-842.
| Crossref | Google Scholar | PubMed |
Fedorova LV, Raju V, El-Okdi N, Shidyak A, Kennedy DJ, Vetteth S, Giovannucci DR, Bagrov AY, Fedorova OV, Shapiro JI, Malhotra D (2009) The cardiotonic steroid hormone marinobufagenin induces renal fibrosis: implication of epithelial-to-mesenchymal transition. American Journal of Physiology-Renal Physiology 296(4), F922-F934.
| Crossref | Google Scholar | PubMed |
Friedman JM (2019) Leptin and the endocrine control of energy balance. Nature Metabolism 1, 754-764.
| Crossref | Google Scholar | PubMed |
Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395(6704), 763-770.
| Crossref | Google Scholar | PubMed |
George EM, Granger JP (2011) Endothelin: key mediator of hypertension in preeclampsia. American Journal of Hypertension 24(9), 964-969.
| Crossref | Google Scholar | PubMed |
Ghadhanfar E, Alsalem A, Al-Kandari S, Naser J, Babiker F, Al-Bader M (2017) The role of ACE2, angiotensin-(1–7) and Mas1 receptor axis in glucocorticoid-induced intrauterine growth restriction. Reproductive Biology and Endocrinology 15(1), 97.
| Crossref | Google Scholar | PubMed |
Gilson GJ, Graves SW, Qualls CR, Curet LB (1997) Digoxin-like Immunoreactive substance and sodium-potassium-adenosine triphosphatase inhibition in normal pregnancy: a longitudinal study. Obstetrics & Gynecology 89(5), 743-746.
| Crossref | Google Scholar | PubMed |
González AR, Phelps SJ, Cochran EB, Sibai BM (1987) Digoxin-like immunoreactive substance in pregnancy. American Journal of Obstetrics and Gynecology 157(3), 660-664.
| Crossref | Google Scholar | PubMed |
Graves SW (1987) The possible role of digitalislike factors in pregnancy-induced hypertension. Hypertension 10(5_pt_2), I84-I86.
| Crossref | Google Scholar | PubMed |
Gusdon JP, Jr, Buckalew VM, Jr, Hennessy JF (1984) A digoxin-like immunoreactive substance in preeclampsia. American Journal of Obstetrics and Gynecology 150(1), 83-85.
| Crossref | Google Scholar | PubMed |
Haffejee F, Naicker T, Singh M, Kharsany ABM, Adhikari M, Singh R, Maharaj N, Moodley J (2017) Placental leptin mRNA expression and serum leptin levels in pre-eclampsia associated with HIV infection. Journal of Obstetrics and Gynaecology 37(1), 48-52.
| Crossref | Google Scholar | PubMed |
Hall JE, Hildebrandt DA, Kuo J (2001) Obesity hypertension: role of leptin and sympathetic nervous system. American Journal of Hypertension 14(6), S103-S115.
| Crossref | Google Scholar | PubMed |
Haller ST, Drummond CA, Yan Y, Liu J, Tian J, Malhotra D, Shapiro JI (2014) Passive immunization against marinobufagenin attenuates renal fibrosis and improves renal function in experimental renal disease. American Journal of Hypertension 27(4), 603-609.
| Crossref | Google Scholar | PubMed |
Hassan MJM, Bakar NS, Aziz MA, Basah NK, Singh HJ (2020) Leptin-induced increase in blood pressure and markers of endothelial activation during pregnancy in Sprague Dawley rats is prevented by resibufogenin, a marinobufagenin antagonist. Reproductive Biology 20(2), 184-190.
| Crossref | Google Scholar | PubMed |
He F, Guan P, Liu Q, Crabtree D, Peng L, Wang H (2017) The relationship between obesity and body compositions with respect to the timing of puberty in Chongqing adolescents: a cross-sectional study. BMC Public Health 17(1), 664.
| Crossref | Google Scholar | PubMed |
Hendler I, Blackwell SC, Mehta SH, Whitty JE, Russell E, Sorokin Y, Cotton DB (2005) The levels of leptin, adiponectin, and resistin in normal weight, overweight, and obese pregnant women with and without preeclampsia. American Journal of Obstetrics and Gynecology 193(3 Pt 2), 979-983.
| Crossref | Google Scholar | PubMed |
Herrera E, Lasuncion MA, Huerta L, Martin-Hidalgo A (2000) Plasma leptin levels in rat mother and offspring during pregnancy and lactation. Neonatology 78(4), 315-320.
| Crossref | Google Scholar | PubMed |
Hoggard N, Hunter L, Duncan JS, Williams LM, Trayhurn P, Mercer JG (1997) Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta. Proceedings of the National Academy of Sciences United States of America 94(20), 11073-11078.
| Crossref | Google Scholar | PubMed |
Huby A-C, Antonova G, Groenendyk J, Gomez-Sanchez CE, Bollag WB, Filosa JA, de Chantemèle EJB (2015) Adipocyte-derived hormone leptin is a direct regulator of aldosterone secretion, which promotes endothelial dysfunction and cardiac fibrosis. Circulation 132, 2134-2145.
| Crossref | Google Scholar | PubMed |
Ibrahim HS, Omar E, Froemming GRA, Singh HJ (2013) Leptin increases blood pressure and markers of endothelial activation during pregnancy in rats. BioMed Research International 2013, 298401.
| Crossref | Google Scholar | PubMed |
Ibrahim HS, Froemming GRA, Omar E, Singh HJ (2014) ACE2 activation by xanthenone prevents leptin-induced increases in blood pressure and proteinuria during pregnancy in Sprague–Dawley rats. Reproductive Toxicology 49, 155-161.
| Crossref | Google Scholar | PubMed |
Jin L, Burguera BG, Couce ME, Scheithauer BW, Lamsan J, Eberhardt NL, Kulig E, Lloyd RV (1999) Leptin and leptin receptor expression in normal and neoplastic human pituitary: evidence of a regulatory role for leptin on pituitary cell proliferation. The Journal of Clinical Endocrinology and Metabolism 84(8), 2903-2911.
| Crossref | Google Scholar | PubMed |
Jin L, Zhang S, Burguera BG, Couce ME, Osamura RY, Kulig E, Lloyd RV (2000) Leptin and leptin receptor expression in rat and mouse pituitary cells. Endocrinology 141(1), 333-339.
| Crossref | Google Scholar | PubMed |
Joubert PH, Grossmann M (2001) Local and systemic effects of Na+/K+ATPase inhibition. European Journal of Clinical Investigation 31(Suppl 2), 1-4.
| Crossref | Google Scholar | PubMed |
Junus K, Björk Ragnarsdóttir I, Nordlöf Callbo P, Bergman L, Lager S, Wikström A-K (2022) Elevated mid-pregnancy plasma levels of angiotensin-converting enzyme 2 in women prior to the development of preeclampsia. Scientific Reports 12, 4109.
| Crossref | Google Scholar |
Keppel MH, Piecha G, März W, Cadamuro J, Auer S, Felder TK, Mrazek C, Oberkofler H, Trummer C, Grübler MR, Schwetz V, Verheyen N, Pandis M, Borzan V, Haschke-Becher E, Tomaschitz A, Pilz S (2019) The endogenous cardiotonic steroid Marinobufagenin and decline in estimated glomerular filtration rate at follow-up in patients with arterial hypertension. PLoS ONE 14(2), e0212973.
| Crossref | Google Scholar | PubMed |
Khademi AR, Rahimi G, Mohammadi M (2012) Comparison of physical activity and body mass index in women with and without miscarriage experiences. Advances in Natural and Applied Sciences 6(8), 1336-1348.
| Google Scholar |
Kiess W, Blum WF, Aubert ML (1998) Leptin, puberty and reproductive function: lessons from animal studies and observations in humans. European Journal of Endocrinology 138(1), 26-29.
| Crossref | Google Scholar | PubMed |
La Cava A (2012) Proinflammatory activities of leptin in non-autoimmune conditions. Inflammation & Allergy – Drug Targets (Discontinued) 11(4), 298-302.
| Crossref | Google Scholar | PubMed |
Ladyman SR, Grattan DR (2013) JAK-STAT and feeding. JAK-STAT 2(2), e23675.
| Crossref | Google Scholar | PubMed |
Ladyman SR, Fieldwick DM, Grattan DR (2012) Suppression of leptin-induced hypothalamic JAK/STAT signalling and feeding response during pregnancy in the mouse. Reproduction 144(1), 83-90.
| Crossref | Google Scholar | PubMed |
Lam GK, Hopoate-Sitake M, Adair CD, Buckalew VM, Johnson DD, Lewis DF, Robinson CJ, Saade GR, Graves SW (2013) Digoxin antibody fragment, antigen binding (Fab), treatment of preeclampsia in women with endogenous digitalis-like factor: a secondary analysis of the DEEP Trial. American Journal of Obstetrics and Gynecology 209(2), 119-e1-119-e6.
| Crossref | Google Scholar | PubMed |
Lappas M, Yee K, Permezel M, Rice GE (2005) Release and regulation of leptin, resistin and adiponectin from human placenta, fetal membranes, and maternal adipose tissue and skeletal muscle from normal and gestational diabetes mellitus-complicated pregnancies. Journal of Endocrinology 186(3), 457-465.
| Crossref | Google Scholar | PubMed |
Laredo J, Shah JR, Lu Z-R, Hamilton BP, Hamlyn JM (1997) Angiotensin II stimulates secretion of endogenous ouabain from bovine adrenocortical cells via angiotensin type 2 receptors. Hypertension 29(1), 401-407.
| Crossref | Google Scholar | PubMed |
Lecke SB, Morsch DM, Spritzer PM (2011) Leptin and adiponectin in the female life course. Brazilian Journal of Medical and Biological Research 44(5), 381-387.
| Crossref | Google Scholar | PubMed |
Levy A, Yagil Y, Bursztyn M, Barkalifa R, Scharf S, Yagil C (2008) ACE2 expression and activity are enhanced during pregnancy. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 295(6), R1953-R1961.
| Crossref | Google Scholar | PubMed |
Lopatin DA, Ailamazian EK, Dmitrieva RI, Shpen VM, Fedorova OV, Doris PA, Bagrov AY (1999) Circulating bufodienolide and cardenolide sodium pump inhibitors in preeclampsia. Journal of Hypertension 17(8), 1179-1187.
| Crossref | Google Scholar | PubMed |
Lopez-Jaramillo P, Barajas J, Rueda-Quijano SM, Lopez-Lopez C, Felix C (2018) Obesity and preeclampsia: common pathophysiological mechanisms. Frontiers in Physiology 9, 1838.
| Crossref | Google Scholar | PubMed |
Luangmonkong T, Suriguga S, Mutsaers HAM, Groothuis GMM, Olinga P, Boersema M (2018) Targeting oxidative stress for the treatment of liver fibrosis. In ‘Reviews of physiology, biochemistry and pharmacology. Vol. 175’. (Eds B Nilius, P de Tombe, T Gudermann, R Jahn, R Lill) pp. 71–102. (Springer) doi:10.1007/112_2018_10
Lv W, Booz GW, Fan F, Wang Y, Roman RJ (2018) Oxidative stress and renal fibrosis: recent insights for the development of novel therapeutic strategies. Frontiers in Physiology 9, 105.
| Crossref | Google Scholar | PubMed |
Malik IA, Durairajanayagam D, Singh HJ (2019) Leptin and its actions on reproduction in males. Asian Journal of Andrology 21, 296-299.
| Crossref | Google Scholar |
Mann DR, Akinbami MA, Gould KG, Castracane VD (2002) Leptin and thyroxine during sexual development in male monkeys: effect of neonatal gonadotropin-releasing hormone antagonist treatment and delayed puberty on the developmental pattern of leptin and thyroxine secretion. European Journal of Endocrinology 146(6), 891-898.
| Crossref | Google Scholar | PubMed |
Martins FF, Aguila MB, Mandarim-de-Lacerda CA (2017) Impaired steroidogenesis in the testis of leptin-deficient mice (ob/ob –/–). Acta Histochemica 119(5), 508-515.
| Crossref | Google Scholar | PubMed |
Martínez-Abundis E, González-Ortiz M, Pascoe-González S (2000) Serum leptin levels and the severity of preeclampsia. Archives of Gynecology and Obstetrics 264, 71-73.
| Crossref | Google Scholar |
Matsuda J, Yokota I, Iida M, Murakami T, Naito E, Ito M, Shima K, Kuroda Y (1997) Serum leptin concentration in cord blood: relationship to birth weight and gender. The Journal of Clinical Endocrinology & Metabolism 82(5), 1642-1644.
| Crossref | Google Scholar | PubMed |
Mavrakanas TA, Gariani K, Martin P-Y (2014) Mineralocorticoid receptor blockade in addition to angiotensin converting enzyme inhibitor or angiotensin II receptor blocker treatment: an emerging paradigm in diabetic nephropathy: a systematic review. European Journal of Internal Medicine 25(2), 173-176.
| Crossref | Google Scholar | PubMed |
Maymó JL, Pérez AP, Sánchez-Margalet V, Dueñas JL, Calvo JC, Varone CL (2009) Up-regulation of placental leptin by human chorionic gonadotropin. Endocrinology 150(1), 304-313.
| Crossref | Google Scholar | PubMed |
Maymó JL, Pérez Pérez A, Gambino Y, Calvo JC, Sánchez-Margalet V, Varone CL (2011) Review: leptin gene expression in the placenta: regulation of a key hormone in trophoblast proliferation and survival. Placenta 32, S146-S153.
| Crossref | Google Scholar | PubMed |
Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD (2009) Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. Journal of the American Society of Nephrology 20(12), 2641.
| Crossref | Google Scholar | PubMed |
Merrill DC, Karoly M, Chen K, Ferrario CM, Brosnihan KB (2002) Angiotensin-(1–7) in normal and preeclamptic pregnancy. Endocrine 18(3), 239-246.
| Crossref | Google Scholar | PubMed |
Mise H, Sagawa N, Matsumoto T, Yura S, Nanno H, Itoh H, Nakao K (1998) Augmented placental production of leptin in preeclampsia: possible involvement of placental hypoxia. Journal of Clinical Endocrinology & Metabolism 83(9), 3225-3229.
| Crossref | Google Scholar | PubMed |
Mix H, Widjaja A, Jandl O, Cornberg M, Kaul A, Göke M, Beil W, Kuske M, Brabant G, Manns MP, Wagner S (2000) Expression of leptin and leptin receptor isoforms in the human stomach. Gut 47(4), 481-486.
| Crossref | Google Scholar | PubMed |
Molin J, Vanky E, Løvvik TS, Dehlin E, Bixo M (2022) Gestational weight gain, appetite regulating hormones, and metformin treatment in polycystic ovary syndrome: a longitudinal, placebo-controlled study. BJOG: An International Journal of Obstetrics & Gynaecology 129(7), 1112-1121.
| Crossref | Google Scholar | PubMed |
Most J, Dervis S, Haman F, Adamo KB, Redman LM (2019) Energy intake requirements in pregnancy. Nutrients 11(8), 1812.
| Crossref | Google Scholar | PubMed |
Mounzih K, Lu R, Chehab FF (1997) Leptin treatment rescues the sterility of genetically obese ob/ob males. Endocrinology 138(3), 1190-1193.
| Crossref | Google Scholar | PubMed |
Mudgett JS, Ding J, Guh-Siesel L, Chartrain NA, Yang L, Gopal S, Shen MM (2000) Essential role for p38α mitogen-activated protein kinase in placental angiogenesis. Proceedings of the National Academy of Sciences United States of America 97(19), 10454-10459.
| Crossref | Google Scholar | PubMed |
Myatt L, Cui X (2004) Oxidative stress in the placenta. Histochemistry and Cell Biology 122(4), 369-382.
| Crossref | Google Scholar | PubMed |
Nadeau V, Charron J (2014) Essential role of the ERK/MAPK pathway in blood–placental barrier formation. Development 141(14), 2825-2837.
| Crossref | Google Scholar | PubMed |
Narula S, Yusuf S, Chong M, Ramasundarahettige C, Rangarajan S, Bangdiwala SI, van Eikels M, Leineweber K, Wu A, Pigeyre M, Paré G (2020) Plasma ACE2 and risk of death or cardiometabolic diseases: a case–cohort analysis. The Lancet 396, 968-976.
| Crossref | Google Scholar | PubMed |
Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GFM (2009) Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clinical Journal of the American Society of Nephrology 4(3), 542-551.
| Crossref | Google Scholar | PubMed |
Neves LAA, Stovall K, Joyner JN, Valdés G, Gallagher PE, Ferrario CM, Merrill DC, Brosnihan KB (2008) ACE2 and ANG-(1–7) in the rat uterus during early and late gestation. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 294(1), R151-R161.
| Crossref | Google Scholar |
Nieuwenhuis D, Pujol-Gualdo N, Arnoldussen IAC, Kiliaan AJ (2020) Adipokines: a gear shift in puberty. Obesity Reviews 21(6), e13005.
| Crossref | Google Scholar | PubMed |
Obeidat RA, Abdo N, Sakee B, Alghazo S, Jbarah OF, Hazaimeh EA, Albeitawi S (2021) Maternal and fetal serum leptin levels and their association with maternal and fetal variables and labor: a cross-sectional study. Annals of Medicine and Surgery 72, 103050.
| Crossref | Google Scholar | PubMed |
Odle AK, Akhter N, Syed MM, Allensworth-James ML, Beneš H, Melgar Castillo AI, MacNicol MC, MacNicol AM, Childs GV (2018) Leptin regulation of gonadotrope gonadotropin-releasing hormone receptors as a metabolic checkpoint and gateway to reproductive competence. Frontiers in Endocrinology 8, 367.
| Crossref | Google Scholar | PubMed |
Oehme NHB, Roelants M, Bruserud IS, Madsen A, Bjerknes R, Rosendahl K, Juliusson PB (2021) Low BMI, but not high BMI, influences the timing of puberty in boys. Andrology 9(3), 837-845.
| Crossref | Google Scholar | PubMed |
Ogein OO, Okunowo AA, Olorunfemi G, Osunwusi B, Adegbola O (2023) Association between maternal serum leptin level and preterm birth among parturients in Lagos, Nigeria. Archives of Obstetrics and Gynaecology 4(2), 34-40.
| Crossref | Google Scholar |
Ogura K, Irahara M, Kiyokawa M, Tezuka M, Matsuzaki T, Yasui T, Kamada M, Aono T (2001) Effects of leptin on secretion of LH and FSH from primary cultured female rat pituitary cells. European Journal of Endocrinology 144(6), 653-658.
| Crossref | Google Scholar | PubMed |
Otero M, Lago R, Lago F, Casanueva FF, Dieguez C, Gómez-Reino JJ, Gualillo O (2005) Leptin, from fat to inflammation: old questions and new insights. FEBS Letters 579(2), 295-301.
| Crossref | Google Scholar | PubMed |
Palei AC, Spradley FT, Granger JP (2015) Chronic hyperleptinemia results in the development of hypertension in pregnant rats. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 308(10), R855-R861.
| Crossref | Google Scholar | PubMed |
Park H-K, Ahima RS (2015) Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism 64(1), 24-34.
| Crossref | Google Scholar | PubMed |
Patel VB, Zhong J-C, Grant MB, Oudit GY (2016) Role of the ACE2/angiotensin 1–7 axis of the renin–angiotensin system in heart failure. Circulation Research 118(8), 1313-1326.
| Crossref | Google Scholar | PubMed |
Peng M, Yang M, Ding Y, Yu L, Deng Y, Lai W, Hu Y (2018) Mechanism of endogenous digitalis-like factor–induced vascular endothelial cell damage in patients with severe preeclampsia. International Journal of Molecular Medicine 41(2), 985-994.
| Crossref | Google Scholar | PubMed |
Pérez-Pérez A, Sánchez-Jiménez F, Maymó J, Dueñas JL, Varone C, Sánchez-Margalet V (2015) Role of leptin in female reproduction. Clinical Chemistry and Laboratory Medicine 53(1), 15-28.
| Crossref | Google Scholar | PubMed |
Pérez-Pérez A, Toro A, Vilariño-García T, Maymó J, Guadix P, Duenas JL, Sánchez-Margalet V (2018) Leptin action in normal and pathological pregnancies. Journal of Cellular and Molecular Medicine 22(2), 716-727.
| Crossref | Google Scholar | PubMed |
Pop VJ, Biondi B, Wijnen HA, Kuppens SM, LVader H (2013) Maternal thyroid parameters, body mass index and subsequent weight gain during pregnancy in healthy euthyroid women. Clinical Endocrinology 79(4), 577-583.
| Crossref | Google Scholar | PubMed |
Puschett JB, Agunanne E, Uddin MN (2010) Marinobufagenin, resibufogenin and preeclampsia. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease 1802(12), 1246-1253.
| Crossref | Google Scholar | PubMed |
Quennell JH, Mulligan AC, Tups A, Liu X, Phipps SJ, Kemp CJ, Herbison AE, Grattan DR, Anderson GM (2009) Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology 150(6), 2805-2812.
| Crossref | Google Scholar | PubMed |
Reitman ML, Bi S, Marcus-Samuels B, Gavrilova O (2001) Leptin and its role in pregnancy and fetal development: an overview. Biochemical Society Transactions 29(2), 68-72.
| Crossref | Google Scholar | PubMed |
Roberts JM, Bodnar LM, Patrick TE, Powers RW (2011) The role of obesity in preeclampsia. Pregnancy Hypertension: an International Journal of Women’s Cardiovascular Health 1(1), 6-16.
| Crossref | Google Scholar | PubMed |
Sagawa N, Yura S, Itoh H, Kakui K, Takemura M, Nuamah MA, Ogawa Y, Masuzaki H, Nakao K, Fujii S (2002) Possible role of placental leptin in pregnancy: a review. Endocrine 19(1), 65-72.
| Crossref | Google Scholar | PubMed |
Saleh L, Verdonk K, Visser W, van den Meiracker AH, Danser AHJ (2016) The emerging role of endothelin-1 in the pathogenesis of pre-eclampsia. Therapeutic Advances in Cardiovascular Disease 10(5), 282-293.
| Crossref | Google Scholar | PubMed |
Santos RAS, Ferreira AJ, Verano-Braga T, Bader M (2013) Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin-angiotensin system. Journal of Endocrinology 216(2), R1-R17.
| Crossref | Google Scholar | PubMed |
Schanton M, Maymó JL, Pérez-Pérez A, Sánchez-Margalet V, Varone CL (2018) Involvement of leptin in the molecular physiology of the placenta. Reproduction 155, R1-R12.
| Crossref | Google Scholar |
Sferruzzi-Perri AN, Vaughan OR, Forhead AJ, Fowden AL (2013) Hormonal and nutritional drivers of intrauterine growth. Current Opinion in Clinical Nutrition and Metabolic Care 16(3), 298-309.
| Crossref | Google Scholar | PubMed |
Shalitin S, Phillip M (2003) Role of obesity and leptin in the pubertal process and pubertal growth: a review. International Journal of Obesity 27(8), 869-874.
| Crossref | Google Scholar | PubMed |
Shekhawat PS, Garland JS, Shivpuri C, Mick GJ, Sasidharan P, Pelz CJ, McCormick KL (1998) Neonatal cord blood leptin: its relationship to birth weight, body mass index, maternal diabetes, and steroids. Pediatric Research 43(3), 338-343.
| Crossref | Google Scholar | PubMed |
Shimizu H, Shimomura Y, Hayashi R, Ohtani K, Sato N, Futawatari T, Mori M (1997) Serum leptin concentration is associated with total body fat mass, but not abdominal fat distribution. International Journal of Obesity 21(7), 536-541.
| Crossref | Google Scholar | PubMed |
Simanjuntak MK, Idris I, Sunarno I, Arifuddin S, Sinrang AW (2021) Mean arterial pressure and the endothelin-1 levels in preeclampsia. Gaceta Sanitaria 35(Suppl 2), S242-S244.
| Crossref | Google Scholar | PubMed |
Singh HJ, Rahman A, Larmie ET, Nila A (2001) Endothelin-l in feto-placental tissues from normotensive pregnant women and women with pre-eclampsia. Acta Obstetricia et Gynecologica Scandinavica 80(2), 99-103.
| Crossref | Google Scholar | PubMed |
Singh HJ, Abu Bakar A, Che Romli A, Nila A (2005) Raised leptin concentrations in feto-placental tissues from women with preeclampsia. Hypertension in Pregnancy 24(2), 191-199.
| Crossref | Google Scholar | PubMed |
Skrypnik D, Adamczak L, Zawiejska A, Gutaj P, Walkowiak M, Wender-Ozegowska E, Bogdanski P (2022) Leptin and vascular endothelial growth factor A: a cross-talk in obese women with gestational diabetes and with diabetes in pregnancy – a cohort study. Journal of Physiology and Pharmacology 73(3), 377-393.
| Crossref | Google Scholar | PubMed |
Smith-Kirwin SM, O’Connor DM, Johnston J, et al. (1998) Leptin expression in human mammary epithelial cells and breast milk. The Journal of Clinical Endocrinology & Metabolism 83(5), 1810.
| Crossref | Google Scholar |
Socha MW, Chmielewski J, Pietrus M, Wartęga M (2023) Endogenous digitalis-like factors as a key molecule in the pathophysiology of pregnancy-induced hypertension and a potential therapeutic target in preeclampsia. International Journal of Molecular Sciences 24(16), 12743.
| Crossref | Google Scholar | PubMed |
Solomon CG, Seely EW (2001) Brief review: hypertension in pregnancy: a manifestation of the insulin resistance syndrome? Hypertension 37(2), 232-239.
| Crossref | Google Scholar | PubMed |
Spradley FT, Palei AC, Granger JP (2015) Increased risk for the development of preeclampsia in obese pregnancies: weighing in on the mechanisms. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 309(11), R1326-R1343.
| Crossref | Google Scholar | PubMed |
Stefaniak M, Dmoch-Gajzlerska E (2022) Maternal serum and cord blood leptin concentrations at delivery in normal pregnancies and in pregnancies complicated by intrauterine growth restriction. Obesity Facts 15(1), 62-69.
| Crossref | Google Scholar | PubMed |
Stefaniak M, Dmoch-Gajzlerska E, Mazurkiewicz B, Gajzlerska-Majewska W (2019) Maternal serum and cord blood leptin concentrations at delivery. PLoS ONE 14(11), e0224863.
| Crossref | Google Scholar | PubMed |
Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD (1998) A leptin missense mutation associated with hypogonadism and morbid obesity. Nature Genetics 18(3), 213-215.
| Crossref | Google Scholar | PubMed |
Słabuszewska-Jóźwiak A, Malinowska M, Kloska A, Jakóbkiewicz-Banecka J, Gujski M, Bojar I, Raczkiewicz D, Jakiel G (2021) Global changes of 5-mC/5h-mC ratio and methylation of adiponectin and leptin gene in placenta depending on mode of delivery. International Journal of Molecular Sciences 22(6), 3195.
| Crossref | Google Scholar | PubMed |
Tamanna S, Clifton VL, Rae K, van Helden DF, Lumbers ER, Pringle KG (2020) Angiotensin converting enzyme 2 (ACE2) in pregnancy: preeclampsia and small for gestational age. Frontiers in Physiology 11, 590787 Erratum in: Frontiers in Physiology 2021, 12: 692761.
| Crossref | Google Scholar | PubMed |
Tamanna S, Lumbers ER, Morosin SK, Delforce SJ, Pringle KG (2021) ACE2: a key modulator of the renin-angiotensin system and pregnancy. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 321(6), R833-R843.
| Crossref | Google Scholar | PubMed |
Taylor RN, Varma M, Teng NN, Roberts JM (1990) Women with preeclampsia have higher plasma endothelin levels than women with normal pregnancies. The Journal of Clinical Endocrinology & Metabolism 71(6), 1675-1677.
| Crossref | Google Scholar | PubMed |
Taylor BD, Ness RB, Olsen J, Hougaard DM, Skogstrand K, Roberts JM, Haggerty CL (2015) Serum leptin measured in early pregnancy is higher in women with preeclampsia compared with normotensive pregnant women. Hypertension 65(3), 594-599.
| Crossref | Google Scholar | PubMed |
Teppa RJ, Ness RB, Crombleholme WR, Roberts JM (2000) Free leptin is increased in normal pregnancy and further increased in preeclampsia. Metabolism 49(8), 1043-1048.
| Crossref | Google Scholar | PubMed |
Tian J, Shidyak A, Periyasamy SM, Haller S, Taleb M, El-Okdi N, Elkareh J, Gupta S, Gohara S, Fedorova OV, Cooper CJ, Xie Z, Malhotra D, Bagrov AY, Shapiro JI (2009) Spironolactone attenuates experimental uremic cardiomyopathy by antagonizing marinobufagenin. Hypertension 54-6 1313-1320 Erratum in: Hypertension 2011, 57(3): e13.
| Crossref | Google Scholar | PubMed |
True C, Takahashi D, Kirigiti M, Lindsley SR, Moctezuma C, Arik A, Smith MS, Kievit P, Grove KL (2017) Arcuate nucleus neuropeptide coexpression and connections to gonadotrophin-releasing hormone neurones in the female rhesus macaque. Journal of Neuroendocrinology 29(6), 1-15.
| Crossref | Google Scholar | PubMed |
Tsai P-JS, Davis J, Bryant-Greenwood G (2015) Systemic and placental leptin and its receptors in pregnancies associated with obesity. Reproductive Sciences 22(2), 189-197.
| Crossref | Google Scholar | PubMed |
Uddin MN, Horvat D, Glaser SS, Danchuk S, Mitchell BM, Sullivan DE, Morris CA, Puschett JB (2008) Marinobufagenin inhibits proliferation and migration of cytotrophoblast and CHO cells. Placenta 29(3), 266-273.
| Crossref | Google Scholar | PubMed |
Uddin MN, Agunanne EE, Horvat D, Puschett JB (2012) Resibufogenin administration prevents oxidative stress in a rat model of human preeclampsia. Hypertension in Pregnancy 31(1), 70-78.
| Crossref | Google Scholar | PubMed |
Vähämiko S, Isolauri E, Laitinen K (2013) Weight status and dietary intake determine serum leptin concentrations in pregnant and lactating women and their infants. British Journal of Nutrition 110(6), 1098-1106.
| Crossref | Google Scholar | PubMed |
Verdich C, Toubro S, Buemann B, Holst JJ, Bülow J, Simonsen L, Søndergaard SB, Christensen NJ, Astrup A (2001) Leptin levels are associated with fat oxidation and dietary-induced weight loss in obesity. Obesity Research 9(8), 452-461.
| Crossref | Google Scholar | PubMed |
Vu HV, Ianosi-Irimie MR, Pridjian CA, Whitbred JM, Durst JM, Bagrov AY, Fedorova OV, Pridjian G, Puschett JB (2005) Involvement of marinobufagenin in a rat model of human preeclampsia. American Journal of Nephrology 25(5), 520-528.
| Crossref | Google Scholar | PubMed |
Wahba IM, Mak RH (2007) Obesity and obesity-initiated metabolic syndrome: mechanistic links to chronic kidney disease. Clinical Journal of the American Society of Nephrology 2(3), 550-562.
| Crossref | Google Scholar | PubMed |
Wang T, Hartzell DL, Flatt WP, Martin RJ, Baile CA (1998) Responses of lean and obese Zucker rats to centrally administered leptin. Physiology & Behavior 65(2), 333-341.
| Crossref | Google Scholar | PubMed |
Wang D, Darling AM, McDonald CR, Perumal N, Liu E, Wang M, Aboud S, Urassa W, Conroy AL, Hayford KT, Liles WC, Kain KC, Fawzi WW (2021) Plasma concentrations of leptin at mid-pregnancy are associated with gestational weight gain among pregnant women in Tanzania: a prospective cohort study. BMC Pregnancy and Childbirth 21(1), 675.
| Crossref | Google Scholar | PubMed |
Ward DR, Dear FM, Ward IA, Anderson SI, Spergel DJ, Smith PA, Ebling FJP (2009) Innervation of gonadotropin-releasing hormone neurons by peptidergic neurons conveying circadian or energy balance information in the mouse. PLoS ONE 4(4), e5322.
| Crossref | Google Scholar | PubMed |
WHO (2011) ‘WHO recommendations for prevention and treatment of pre-eclampsia and eclampsia.’ (World Health Organization) Available at www.who.int/reproductivehealth/publications/maternal_perinatal_health/9789241548335/en/index.html
Woller M, Tessmer S, Neff D, Nguema AA, Roo BV, Waechter-Brulla D (2001) Leptin stimulates gonadotropin releasing hormone release from cultured intact hemihypothalami and enzymatically dispersed neurons. Experimental Biology and Medicine 226(6), 591-596.
| Crossref | Google Scholar | PubMed |
Yamaleyeva LM, Pulgar VM, Lindsey SH, Yamane L, Varagic J, McGee C, daSilva M, Lopes Bonfa P, Gurley SB, Brosnihan KB (2015) Uterine artery dysfunction in pregnant ACE2 knockout mice is associated with placental hypoxia and reduced umbilical blood flow velocity. American Journal of Physiology – Endocrinology and Metabolism 309(1), E84-E94.
| Crossref | Google Scholar | PubMed |
Zeng S, Liu Y, Fan P, Yang L, Liu X (2023) Role of leptin in the pathophysiology of preeclampsia. Placenta 142, 128-134.
| Crossref | Google Scholar | PubMed |
Zhao Y, Hong N, Liu X, Wu B, Tang S, Yang J, Jia W (2014) A novel mutation in leptin gene is associated with severe obesity in Chinese individuals. BioMed Research International 2014, 912052.
| Crossref | Google Scholar | PubMed |
Żelechowska P, Kozłowska E, Pastwińska J, Agier J, Brzezińska-Błaszczyk E (2018) Adipocytokine involvement in innate immune mechanisms. Journal of Interferon & Cytokine Research 38(12), 527-538.
| Crossref | Google Scholar | PubMed |