Emerging Role of Leptin in Vascular and Placental Dysfunction in Preeclampsia

Abstract

Leptin is a well-known metabolic hormone that plays diverse roles in various body functions including growth, reproduction and blood pressure regulation. In pregnancy, leptin produced from the placenta is crucial for insuring proper fetal development and angiogenesis, however, pathological increases in leptin in maternal circulation is strongly associated with vascular endothelial dysfunction and preeclampsia. Leptin has a strong role in fertility and healthy pregnancy, however, numerous clinical reports over the last two decades show that leptin levels pathologically increase in preeclampsia patients independent of metabolic status (i.e. obesity). Despite this strong correlation, the role of leptin in preeclampsia is largely unexplored compared to other biomarkers likely due to differences in placental leptin production amongst mammals. Emerging literature has recently begun to shed light on this hormone in preeclampsia pathogenesis and uncovered some key mechanisms whereby pathologically elevated leptin production leads to cardiovascular complications for pregnant women.

Introduction

Leptin is a 16kDa peptide whose name has become almost synonymous with obesity. In nonpregnant individuals the primary governor of systemic leptin levels is the production of adipose-derived leptin, its most prominent source, and its levels correlate with adipose tissue mass. Leptin activity is mediated primarily through the long form of the leptin receptor (ObR gene) whose expression is fairly ubiquitous across all tissues, with the short form having lesser-known roles. Leptin has diverse roles in various tissues including to increase metabolism and suppress appetite,¹ promote growth,^2–4 initiate inflammation (reviewed by⁵), as well as regulate insulin and glucose homeostasis (reviewed by⁶), blood pressure (reviewed by⁷), and sympathetic activity⁸(reviewed by⁹).

Notably, leptin is a highly important hormone for fertility and pregnancy. Studies in rodents and humans demonstrate that endogenous leptin production is required for female puberty, cycling and conception^10,11(reviewed by^12–14). Smaller mammals do not produce leptin in placenta^15–17. However, in humans, trophoblasts are the placenta-specific cell-type that forms the bulk of the organ and facilitates its endocrine function, and these cells become a prominent leptin factory and progressively produce high levels of leptin across the gestation period. Therefore, homeostasis of leptin levels is likely a highly important factor for a healthy pregnancy. However, pathologically elevated placental production of leptin in pregnancy is strongly associated with adverse pregnancy outcomes, most notably preeclampsia. The aim of this review is to outline the emerging role of leptin in preeclampsia including candidate mechanisms whereby leptin may promote preeclampsia disease. This synopsis is intended as a tool to identify the state of the field and provide a resource to future studies of leptin in preeclampsia into these and other mechanisms.

Leptin is a reproductive hormone in women, facilitating fetal growth in pregnancy

Leptin is a sexually dimorphic hormone, favoring a higher level of leptin per unit of body mass index (BMI) in women compared to men (reviewed by¹⁸). Sufficient leptin production is required for the initiation and maintenance of normal pregnancy. Female mice deficient in the leptin gene (ob/ob) do not undergo puberty and are cycling arrested.¹⁹ Starvation also induces reproductive arrest in rodents that is restored by exogenous leptin supplementation.^20,21 It is believed that leptin plays a role as a “gatekeeper” for puberty/fertility, signaling the adequate positive energy balance (i.e. adipose tissue) needed to sustain a pregnancy (reviewed by²²). The literature also suggests leptin has roles in early pregnancy, with recent studies showing leptin facilitates formation of the placenta and prevents toxicity-induced trophoblast apoptosis, thereby stabilizing placental development.^23,24 Recent reports also show that leptin promotes trophoblast invasion^25–27 dependent on the gestational age and level of leptin.²⁶ Placental trophoblasts are also highly potent leptin-producing cells^28–31 and circulating leptin levels in both the maternal and fetal circulation rise progressively across pregnancy due to increasing trophoblast leptin production as the placenta grows. In lean women, placental leptin production results in a steadily increasing leptin circulating level over pregnancy.²⁹ However, in obese women, leptin levels are highly elevated above those in lean women across all trimesters, with adipose tissue serving as the primary source of leptin.³²

In the fetal circulation, leptin acts as a growth hormone. In non-hypertensive pregnancy, high umbilical cord leptin levels are associated with elevated fetal and placenta weight at birth (macrosomia), independent of body mass index,^33,34 while low cord leptin is associated with fetal growth restriction.^35–42 A few older reports indicate that leptin promotes fetal growth by inhibition and stimulation of fetal somatostatin⁴³ and pituitary growth hormone,⁴⁴ respectively. It is unlikely that leptin readily crosses the placenta, as fetal levels of leptin do not often correlate with maternal levels,⁴⁵ although this remains for debate and both the fetal and maternal interface of the placenta produce leptin (reviewed by⁴⁶). Therefore, it is apparent that placental leptin production feeds both the maternal and fetal circulation. These data indicate that the leptin produced for the fetus is triggered to stimulate growth, however, excessive leptin released into maternal circulation may have pathological consequences.

Emerging role of leptin in Preeclampsia

Preeclampsia is a placental-derived disease that manifests as mid-late gestation hypertension with the development of end organ dysfunction peripheral to the placenta⁴⁷ (reviewed by^48,49). Preeclampsia is a growing clinical burden whose rates are increasing in the US and it is a major contributor to adverse maternal and fetal pregnancy outcomes. For more than two decades, the clinical literature has reported strong associations of maternal circulating leptin levels with preeclampsia, as featured in a systematic table review in Table 1.^50–69 Some highlighted studies include Plowden et al., who showed in their prospective study on more than 1000 female subjects, higher preconception leptin levels were associated with hypertensive disorders and gestational diabetes even after controlling for age and BMI⁷⁰ which is consistent with other studies^71–75. These correlations may be restricted to latter trimesters of pregnancy, as pre-pregnancy and 1^st trimester leptin levels, do not accurately predict preeclamptic pregnancy when normalized for BMI in many cohorts.^51,52,59 Leptin levels characteristically increase in preeclampsia patients at or after the onset of symptoms (>20 weeks gestation) compared to normal pregnant patients independent of BMI in many studies^{51–54,56,57,59,65,67,68,76,77}, and are associated with preeclampsia severity.⁵³ Therefore, leptin may or may not be a candidate biomarker for early detection of preeclampsia prior to symptom onset. One study concluded that the addition of leptin level to the soluble FMS-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PLGF) ratio, a recently FDA-approved prognostic test for preeclampsia onset, strengthens the predictive ability than either measure alone.⁶⁶ Notably, it has long been shown that placental leptin production increases in preeclampsia patients compared to non-preeclampsia pregnancies,^68,78 likely accounting for the lack of association of leptin levels with BMI in many cohorts. Therefore, one may speculate that the condition of placental dysfunction in preeclampsia prompts the placenta to produce the growth hormone leptin to improve fetal growth.

Table 1.

Summary of clinical cohorts in which leptin and preeclampsia are linked

Summary of studies involving leptin and preeclampsia
Reference	Study design	Inclusion and exclusion criteria	Cases/Exposure					Controls/No exposure					Lab value studied/Outcome measure	Results		Conclusions
			Description	N	BMI	GA at delivery	Neonatal BW	Description	N	BMI	GA at delivery	Neonatal BW		Cases	Controls
Nugrahani et al. 2024 (45)	Systemic review and meta-analysis	Included studies in English, with original quantitative data, and published in peer-reviewed journal; Excluded were reviews or an abstract of grey literature, or published prior to 2014	Obese pregnant women with PE	3 studies included, 113 patients with PE	N/A	35.6 weeks	2330g	Obese pregnant women without PE	3 studies included, 2,452 patients without PE	N/A	38.9 weeks	3414g	Mean difference of leptin and adiponectin levels between cases and controls	Leptin and adiponectin levels were higher and lower, respectively, than controls	Leptin and adiponectin levels were higher and lower, respectively, than controls	In all 3 studies, leptin levels were elevated in PE cases compared to controls, while adiponectin levels were lower in PE than controls.
de Knegt et al. 2024 (46)	Case-control (sub-study of larger study)	Singleton pregnancies	Patients who developed PE	126	24.0*	275.5 days*	relative BW 91.39%*	Age-, parity-, and gestational age-matched	297	21.7*	284 days*	relative BW 98.42%*	Adiponectin/leptin (A/L) ratio in 1st trimester	A/L 0.17*	A/L 0.32*	A/L ratio was lower in PE pregnancies; PE negatively associated with log A/L ratio independent of maternal BMI; PE and leptin negatively associated with birth weight, but leptin alone not correlated with PE; no correlation between A/L ratio and severity of PE
Garces et al., 2023 (47)	Nested case-control study within a prospective observational study	Singleton pregnancies; excluded patients with pre-pregnancy HTN, diabetes, obesity, and other chronic conditions	Patients with mild PE	20	2nd trimester 26.4; 3rd trimester 29.4	37.6 weeks*	2762g*	Healthy pregnancies	46	2nd trimester 24.6; 3rd trimester 26.5	39.2 weeks*	3099g*	Free leptin index (FLI) = circulating leptin/soluble leptin receptor in each trimester and 3 months postpartum	2nd trimester FLI 13.5*; 3rd trimester FLI 18.1*	2nd trimester FLI 8.6*; 3rd trimester FLI 9.4*	In the 2nd and 3rd trimesters, FLI was significantly higher in patients who went on to develop mild PE compared to controls; PE group progressively increased FLI in 2nd and 3rs trimesters compared to 1st; Control group had significantly higher sOB-R levels in 2nd and 3rd trimesters compared to PE.
Okafor et al., 2023 (48)	Cross-sectional study	Singleton pregnancies 18–45yo; excluded cHTN, diabetes, retroviral and renal disease, smoking or malignancy in past 6 months	Patients with PE	60	30.83	33.83 weeks*	2131.18g*	Age- and BMI-matched normotensive pregnant patients	60	29.99	37.65 weeks*	3171g*	Maternal (at time of labor/cesarean section) and umbilical cord (prior to cleavage of placenta) sera levels of leptin (ng/mL)	Maternal PE 24.88*, severe PE 25.91*, mild PE 22.83*, umbilical cord 6.43*	Maternal 15.03*, umbilical cord 7.27*	Maternal serum leptin significantly increased and umbilical cord levels significantly decreased in PE compared to controls; maternal serum leptin level was significantly higher in those with severe PE compared to mild PE.
Peltokorpi et al., 2022 (49)	Nested case-control	All patients of a monitored Finnish cohort who developed pregnancies	Patients with GDM and/or gHTN/PE (PE patients were defined as having protenuria)	GDM 71, gHTN 27, GDM+PE 6	GDM 24.7, gHTN 26.1	N/A	N/A	All pregnant women not selected for cases groups	All controls 201, GDM control 142, GDM+PE control 54	All controls 22.6	N/A	N/A	Maternal serum leptin (ng/mL) prior to pregnancy	GDM 16.4*, gHTN/PE 16.4, gHTN/PE+GDM 16.1	11.5*	Leptin levels are higher in nonpregnant patients who would go on to develop GDM or gHTN/PE, however, when normalized for BMI only in GDM group.
Schoots et al., 2021 (50)	Prospective pilot study	18–40 years old, 24–36 weeks gestational age; patients with proteinuria excluded	Patients with severe FGR (<3rd %tile); patients with severe FGR + gHTN	Severe FGR 14; Severe FGR + gHTN 11	Severe FGR 24.3, Severe FGR + gHTN 30.1	Severe FGR 37.0 weeks; Severe FGR + gHTN 30.9 weeks	Severe FGR 2168.6g; Severe FGR + gHTN 1205g	Healthy pregnancies	23	25.4	39.2 weeks	3390.7g	Collected at time of inclusion, median of 33.4* weeks in FGR group, 29.4* weeks in FGR + gHTN group, and 33.0 weeks in control group: sFlt-1/PlGF ratio, leptin (pg/mL)	FGR: sFlt-1/PlGF 47.6*, leptin 12583; FGR + gHTN: sFlt-1/PlGF 1400.7*, leptin 47681*	sFlt-1/PlGF 5.0*, leptin 11294*	Similar to sFlt-1/PLGF ratio, leptin was significantly higher in FGR + gHTN, but not FGR alone, compared to controls. In differentiating FGR + gHTN from FGR only and controls leptin (AUC 0.83 and 0.94 respectively) showed discriminitive capacity.
Rao et al., 2021 (51)	Prospective cohort study	Singleton pregnancies, >18 years old, BMI >18.5 and <23; excluded cHTN, gHTN, diabetes, renal disease	Patients with PE	60	18.5–22.9, 44 patients; 23–24.9, 13 patients; >25, 3 patients	N/A	N/A	Age- and gestation-matched normotensive, nonproteinuric patients	60	18–22.9, 45 patients; 23–24.9, 12 patients; >25, 3 patients	N/A	N/A	Adiponectin levels (μg/mL), leptin levels (ng/mL), A/L ratio	Adiponectin 9.62; leptin 67.31*; A/L 0.22*	Adiponectin 8.56; leptin 12.54*; A/L 9.80*	No significant difference in adiponectin levels between PE and controls; leptin significantly increased and A/L decreased in PE compared to controls; there was a significant increase in A/L ratio in severe compared to mild PE
Beneventi et al., 2020 (52)	Case-control	Singleton pregnancies; excluded chromosomal/fetal abnormalities, diabetes, cHTN, GDM	Patients with obesity/overweight +/− PE	18 obese/over-weight, 17 obese/over-weight + PE	25–29.9, 11 patients; 30–34.9, 13 patients; >35, 11 patients	39.6 weeks	obesity + PE 2915g*	Lean patients +/− PE	42 lean, 5 lean + PE	<24.9	39.2 weeks	normotensive 3286g*	Leptin (ng/mL) in maternal serum in 1st, 2nd, 3rd trimesters, and cord blood at term	Leptin 3rd trimester values: 28.52* for normotensive group, 40.77* for PE group	Leptin 3rd trimester values: 15.68* for normotensive group, 21.5* for PE group	Patients with obesity/overweight and PE had significantly higher 3rd trimester and cord blood leptin compared to lean patients +/− PE as well as obesity/overweight without PE. Obese/overweight patients had higher 3rd trimester leptin than lean +/−PE.
Hao et al., 2020 (53)	Retrospective cohort from a prospective longitudinal study	>18 years old, 1st trimester at enrollment, singleton patients	Patients who developed PE	14	N/A	36.7 weeks	N/A	Uncomplicated pregnancies with full term deliveries; no history of preterm birth or PE	16	N/A	39.5 weeks	N/A	Assessed difference in mean leptin, sFlt-1, PLGF levels (cases minus controls in pg/mL) at 10–14, 15–25, 26–33, and 27–38 weeks gestation	Leptin at 10–14 weeks 8,858*; s-Flt at 26–33 weeks 2,831*; PlGF at 27–38 weeks −686*		Difference in serum leptin level between cases and controls was significant at 10–14 weeks (higher in cases), 26–33 weeks for s-Flt (higher in cases), and 27–38 weeks for PlGF (higher in controls).
Daskalakis et al., 2020 (54)	Systematic review	Studies that reported serum levels of any adipokine in patients with PE and healthy controls; excluded case reports, small case series, letters to editor, animal studies, and reviews; excluded gHTN	Patients with PE	163 studies total; 91 addressed leptin, 48 addressed adiponectin	N/A	N/A	N/A	Healthy controls, some studies were BMI-matched	163 studies total; 91 addressed leptin, 48 addressed adiponectin	N/A	N/A	N/A	14 adipokines, including leptin (ng/mL) and adiponectin (μg/mL)	Leptin was increased in cases compared to controls in 50 BMI-matched studies and 26 BMI-unmatched studies, decreased in 1 BMI-matched study, and there was no association in 9 BMI-matched and 5 BMI-unmatched studies. Adiponectin was increased in cases compared to controls in 24 BMI-matched studies and 3 BMI-unmatched studies, decreased in 7 BMI-matched and 3 BMI-unmatched studies, and there was no associated in 7 BMI-matched and 4 BMI-unmatched studies.		83.5% of studies reported significantly elevated serum values of leptin in PE, and severe PE was associated with higher values than mild PE. These findings were not affected by obesity
Chandrasekaran et al., 2020 (55)	Case-control	Singleton pregnancies; excluded underweight/overweight, cHTN, pregestational diabetes, autoimmunnne disease, spontaneous preterm labor	Patients with PE	36 obese, 25 normal weight	Obese ≥30; normal weight 18.5–24.9	Obese - 34.1 weeks; normal weight - 34.1 weeks	N/A	Normotensive age-, race-, BMI-matched patients	29 obese, 27 normal weight	Obese ≥30; normal weight 18.5–24.9	N/A	N/A	3rd trimester plasma leptin (ng/mL) and adiponectin (μg/mL)	Obese: adiponectin 17.94, leptin 9.36*; normal weight: adiponectin 34.6; leptin 5.39*	Obese: adiponectin 23.9, leptin 5.87*; normal weight: adiponectin 37.9, leptin 2.01*	Cases had a significantly higher leptin, but not adiponectin, levels compared to controls. Obesity was associated with higher leptin and lower adiponectin compared to normal weight.
Thagaard et al., 2019 (56)	Cohort	Pregnant women in 1st trimester; excluded cHTN	Patients with PE	64 total; 14 normal weight, 35 moderate obesity, 15 severe obesity	Normal weight 18.5–24.9; moderate obesity 20–34.9, severe obesity ≥35	270.6 days*	3090g*	Normotensive controls	2410 total; 1233 normal weight, 800 moderate obesity, 377 severe obesity	Normal weight 18.5–24.9; moderate obesity 20–34.9, severe obesity ≥35	280.3 days*	3580g*	1st trimester serum sample: log adiponectin mean, log leptin mean, log A/L mean	Adiponectin 8.22, leptin 10.15, A/L −1.93	Adiponectin 8.43, leptin 9.92, A/L −1.49	Log concentrations of adiponectin were negatively associated with PE in moderate and severe obese patients, but not in normal weight patients. There was a lower log leptin level in PE obese patients, but not association in PE patients with normal weight or moderate obesity. No association between PE and A/L ratio.
Huda et al., 2017 (57)	Cross-sectional	Singleton, non-laboring patients at term; excluded patients with cardiovascular or metabolic disease	Patients with PE	13	31.1	35.6 weeks*	2330g*	Age- and BMI-matched healthy controls	13	29.6	38.9 weeks*	3414g*	Plasma levels of adiponectin (μg/mL), leptin (mg/mL), sFlt-1 (ng/mL) at term	Adiponectin 9.0, leptin 85, sFlt-1 18.6*	Adiponectin 9.9, leptin 50, sFlt-1 3.4*	There was no significant difference in leptin and adiponectin levels between cases and controls. sFlt-1 was significantly higher in cases compared to controls.
Song et al., 2016 (58)	Case-control	Singleton pregnancies; excluded GDM, fetal death, clinical chorioamnionitis	Patients with PE	74	30.36*	32.86 weeks*	1773.74g*, 49.3% SGA	Healthy, uncomplicated, controls	79	25.92*	39.33 weeks*	3258.92g*, 2.5% SGA	Leptin (ng/mL) and adiponectin (μg/mL) measured at time of PE diagnosis or (GA-matched time for controls)	Leptin 34.23*; adiponectin 9.50	Leptin 15.84*; adiponectin 8.39	Serum leptin levels were significantly higher in cases compared to control; there was no significant difference in leptin level between mild and severe PE; no significant difference was noted in adiponectin level between the cases and controls; leptin correlated with BMI only in controls.
Taylor et al., 2015 (59)	Nested case-control	Primiparous singletons; excluded GDM and HTN	Patients with PE	430	<25 – 58.8%, 25–29.9 – 25.1%*, ≥30 – 16.1%*	≥37 weeks - 78.4%*; <37 weeks - 21.2%*	N/A	Normotensive patients	316	<25 – 77.5%, 25–29.9 – 17.4%*, ≥30 – 5.1%*	≥37 weeks - 96.2%*; <37 weeks - 3.8%*	N/A	Second trimester median maternal plasma leptin (ng/mL) level (median-17 weeks)	30.5*	20.9*	Leptin was significantly higher in cases compared to controls; there was a positive correlation between leptin and PE; BMI was positively correlated with leptin.
Kalinderis et al., 2015 (60)	Case-control	Singleton pregnancies; excluded cHTN, GDM, infectious disease in pregnancy, premature rupture of membranes, active labor, polyhydramnios	Patients with PE	29	31.79	N/A	N/A	Age-, GA-, BMI-matched controls	29	29.23	N/A	N/A	Leptin (ng/mL) in maternal serum collected at admission	Leptin 71.69*; IP-10 138.71	Leptin 34.27*; IP-10 112.17	Leptin was significantly higher in cases compared to controls; this finding remained significant when comparing mild PE and severe PE to controls.
Molvarec et al. 2011 (61)	Case-control	Caucasian women; excluded multifetal gestation, chronic hypertension, diabetes mellitus, autoimmune disease, angiopathy, renal disorder, maternal or fetal infection, fetal congenital anomaly, premature rupture of membranes, hormonal contraception use	Patients with PE	60	29.9*	38 weeks	3125g*	Healthy non-pregnant and pregnant women	60	Non-pregnant 20.8*; Pregnant 25.8*	39 weeks	3450*	Serum leptin (ng/ml) levels and sFlt-1/PLGF ratio collected at 36–37 weeks gestation	Absolute values not given, levels expressed as box-whisker plots	Absolute values not given, levels expressed as box-whisker plots	Leptin levels significantly increased in pregnant patients compared to non-pregnant; leptin levels significantly increased in PE patients compared to non-pregnant and pregnant patients both with and without adjustment for BMI; leptin addition to sFlt-1/PLGF ratio is a significantly better predictor of PE than either measure alone
Herse et al., 2009 (62)	Case-control	Singleton pregnancies; excluded diabetes, fetal anomalies, exposure to magnesium sulfate	Patients with PE	25 severe PE, 7 mild PE	25.93	239.5 days*	2431.3g*	Healthy patients who were either nonpregnant, 1st trimester, 2nd trimester, 3rd trimester	15 nonpregnant, 25 1st trimester, 25 2nd trimester, 30 3rd trimester	3rd trimester group 25.43	3rd trimester group 268.5 days*	3rd trimester group 3171.7g*	Plasma adiponectin (ng/mL) and leptin (ng/mL) concentrations collected at 33.1 weeks in cases and 33.7 in 3rd trimester controls	Adiponectin 33.10*, leptin 0.87*	3rd trimester: adiponectin 38.03*, leptin 0.58*	Adiponectin levels in the 3rd trimester in the control group were significantly elevated compared to nonpregnant, 1st trimester, 2nd trimester, and 3rd trimester PE patients; adiponectin level in 3rd trimester correlated inversely with prepregnancy BMI in controls, but this relationship was not significant in PE group; plasma leptin was significantly higher in PE group compared to 3rd trimester controls; there was a significant decrease in plasma leptin level between 1st and 3rd trimester in control group; no correlation between leptin level and BMI.
Singh et al., 2005 (63)	Case-control	Excluded multiples	Patients with PE	10	N/A	36.1 weeks	3.14 kg	Normotensive age-, race-, parity-matched	10	N/A	38.2 weeks	3.33 kg	Mean leptin concentration (ng/mg) in amnion, chorion, and placenta after vaginal delivery; placental weight (kg)	Amnion 1.15*, chorion 2.19*, placenta 13.95*; 0.58*	Amnion 0.52*, chorion 0.99*, placenta 10.28*; 0.67*	Leptin was significantly higher in all tissues from patients with PE compared to controls; in controls, placental leptin concentration was 10–20x higher than that of amnion and chorion; in PE group, placental leptin concentration was 6–10x higher than that of amnion and chorion
Williams et al., 1999 (64)	Nested-case control	Excluded gHTN and cHTN	Patients with PE	38	25.4*	36.7 weeks*	2823.3g*	Normotensive patients	192	22.8*	38.5 weeks*	3402.6g*	Maternal plasma leptin (ng/mL) level collected 15–22 weeks gestation	20.2*	16.7*	2nd trimester leptin level was significantly higher in cases compared to controls; for controls, 2nd trimester leptin concentration was positively correlated with maternal pre-pregnancy BMI and 2nd trimester BMI; for cases, these values were weakly correlated.

Table 1 - Summary of several studies evaluation leptin and preeclampsia, as well as additional adipokines and placental biomarkers.

Abbreviations: Gestational diabetes, GDM; hypertension, HTN; PE, preeclampsia; gestational age, GA; chronic HTN, cHTN; gestational HTN, gHTN; body mass index, BMI; fetal growth restriction, FGR; soluble FMS-like tyrosine kinase-1, sFlt-1; placental growth factor, PlGF; soluble leptin receptor, sOB-R; not applicable, N/A.

^*indicates the study noted a signficant difference in this measure between cases and controls

Although it is well documented that leptin levels increase in preeclampsia, whether leptin has a functional role in promoting disease is a newer field. Experimental studies demonstrate that leptin promotes cardiovascular disease when produced in excess, in particular increases blood pressure⁷⁹(reviewed by^80,81). To date, there have been only a few experimental studies testing whether leptin promotes hypertension in pregnancy. Studies in 2014 and 2020 by Singh and colleagues showed that leptin administration starting at gestation day (GD)1 of pregnancy increased systolic blood pressure across the pregnancy in rats.^82,83 Palei et al. showed in 2015 that leptin administration to normal pregnant and Reduced Uterine Perfusion Pressure (RUPP) rats with placental ischemia did not increase blood pressure, but decreased fetal weight, fetal survival, vascular smooth muscle relaxation and nitrate/nitrite levels (an indicator of nitric oxide bioavailability).⁸⁴ Our group performed the first experiments of leptin administration to pregnant mice and we showed that leptin infusion at mid-to-end of gestation induces features of preeclampsia in hypertension, fetal growth restriction, endothelial dysfunction and elevations in endothelin-1 expression in placenta⁸⁵ These data demonstrate that leptin is not only associated with preeclampsia but is likely a candidate player in the pathophysiological mechanisms of the condition.

Candidate mechanisms whereby leptin leads to adverse pregnancy outcomes in preeclampsia

Vascular endothelial dysfunction

Leptin receptors are widely expressed, with well-established activity in neurons, hepatocytes and insulin-sensitive tissues. Leptin receptors are a tyrosine kinase receptor with its major intracellular signaling mediated via Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation. Endothelial cells, in particular, express high levels of leptin receptor and preclinical data demonstrate that leptin promotes endothelial dysfunction sex-specifically in females. In males, leptin mediates increases in blood pressure via heightened sympathetic activation which reverts following weight loss and reduced leptin levels^86,87(reviewed by^88,89). On the other hand, in obese females, sympathetic activation is not increased as potently as in males (reviewed by⁹⁰). In females, leptin promotes increases in blood pressure and vascular endothelial dysfunction via activation of systemic mineralocorticoid receptors in both nonpregnancy and pregnancy.^85,91–93 In males, in contrast, deletion of the endothelial leptin receptor does not impact the effect of leptin on blood pressure or sympathetic activity⁹⁴, and may be beneficial to blood pressure regulation.⁹⁵

Importantly, endothelial dysfunction is a hallmark of preeclampsia, characteristically presenting in patients both in mid-gestation and late gestation in preeclampsia patients⁹⁶. We recently showed that leptin may be a crucial element promoting vascular endothelial dysfunction in these patients. In the RUPP mouse model of preeclampsia, mice develop many characteristics of disease including hypertension and fetal growth restriction, however, not vascular endothelial dysfunction.⁹⁷ However, if exogenous leptin is administered to elevate circulating leptin levels, RUPP mice develop endothelial dysfunction.⁹⁷ Therefore, leptin is a candidate mediator for vascular disease in these hypertensive pregnancies.

In both leptin- and RUPP-induced preeclampsia mouse models, deletion of endothelial mineralocorticoid receptors (MR) prevents hypertension and fetal growth restriction.⁸⁵ The mechanisms by which endothelial MR activation leads to vascular dysfunction are multifaceted and include promotion of vascular oxidative stress and inflammation^98,99 (reviewed by⁸⁹) increasing epithelial sodium channel (ENaC)-mediated Ca²⁺-induced vascular stiffness¹⁰⁰ and reducing nitric oxide (NO) bioavailability.^101,102 Recent data suggests that endothelin-1 (ET-1) may be a link between leptin, endothelial MR and endothelial dysfunction. Many clinical and experimental reports demonstrate that the ET-1 system is pathologically activated in preeclamptic patients and ET-1 is a potent vasoconstrictor, primarily produced by endothelial cells and leads to endothelial injury.¹⁰³ In pregnant mice, placental expression of both preproendothelin-1 and endothelin converting enzyme-1 increase in response to leptin infusion, which is prevented by endothelial MR deletion⁸⁵. Others have similarly shown in nonpregnant mice that MR activation¹⁰⁴ and in vitro that leptin¹⁰⁵ increases ET-1 production. Therefore, leptin-induced activation of endothelial MR may be the key preeclampsia pathway that elevates ET-1 and leads to vascular endothelial injury, as described in Figure 1.

Figure 1.

Anti-angiogenic factors

In pregnancy, angiogenic factors play a major role in vascular remodeling, endothelial-derived vascular distensibility and blood pressure regulation (reviewed by⁴⁹). Vascular endothelial growth factor (VEGF) and PLGF are responsible for endothelial cell migration and proliferation through binding to vascular endothelial growth factor receptor (VEGFR)¹⁰⁶ (reviewed by¹⁰⁷). Soluble FMS-like tyrosine kinase-1 (sFlt-1) is a soluble form of VEGFR1 that is known to act as a decoy receptor to VEGF and PLGF thus preventing its binding to VEGFR.¹⁰⁸ sFlt-1 is upregulated generally during pregnancy but is strongly elevated in preeclampsia alongside downregulation of PLGF.^109–111 The strong correlation of sFlt-1/PlGF ratio with the severity of preeclampsia led to the FDA approval of the sFlt/PlGF ratio as a prognostic marker to predict severe features of preeclampsia.^112,113 A ratio of less than 40 suggests the likelihood of developing preeclampsia with severe features is <5%.¹¹²

Whether leptin promotes anti-angiogenic factors is a pertinent question, however, our report suggested that leptin infusion in pregnant mice does not increase placental sFlt-1 or PLGF gene expression⁸⁵. It is possible that these anti-angiogenic factors may precede upregulation of leptin in the preeclamptic placenta. Early-stage preeclampsia is characterized by inadequate angiogenic growth and arterial invasion in the myometrial wall, resulting in insufficient placental perfusion.^114,115 Some have hypothesized that leptin upregulation in preeclampsia is derived from placental insufficiency as a counterregulatory mechanism to improve angiogenesis.^114,116 Leptin stimulates VEGF and VEGFR2 in tumors¹¹⁷ and leptin production is induced by hypoxia in adipose tissues.^118–120 Therefore, leptin upregulation in preeclampsia may be a regulatory feedback to the placental ischemia state. A recent report indicates that late-gestation leptin promotes mitochondrial dysfunction and oxidative stress in the placenta, which may promote placentation impairment early in pregnancy.¹²¹ With this supporting evidence on the crosstalk between leptin and angiogenic factors, it is compelling for the field now to investigate the interactions of leptin, angiogenesis and placental insufficiency to determine the mechanisms whereby these factors may interact with one another and promote adverse maternal-fetal outcomes.

Challenges in leptin studies in nonhuman models

With increasing interest in the effects of leptin on development, cardiovascular regulation, and metabolism during pregnancy, several trials were made to recapitulate hyperleptinemia in rodent models during pregnancy. One hurdle in developing these models is that, unlike humans who produce leptin from both adipose tissue and placenta during pregnancy, our data (unpublished) and others report rodents do not produce leptin in the placenta during pregnancy.^15–17 Larger mammals, such as sheep¹²² and nonhuman primates (reviewed by¹²³) do demonstrate placental leptin expression, therefore, placental leptin is likely an evolutionary adaptation to mammals that have primarily singleton pregnancies. Therefore, exogenous leptin administration is needed in rodents to mimic the preeclampsia-induced plasma level elevation. In addition, leptin-induced effects on appetite are an important consideration in rodent studies. In the Palei et al. study, and to a lesser degree in the Singh studies, rats given leptin during pregnancy experienced pronounced weight loss or were restricted in weight gain.^82–84 Importantly, in pregnant mice, similar to pregnant humans,¹²⁴ appetite suppression by leptin meets swift development of leptin resistance and weight loss is not observed.⁸⁵ Therefore, dosage and administration of leptin and selection of rodent model is an important consideration.

Conclusion and Perspectives

Although leptin is crucial for growth, development and reproduction in humans, pathological maternal leptin upregulation during pregnancy is associated with preeclampsia and adverse fetal outcomes. Although leptin has been seldom explored as a biomarker to predict preeclampsia, one study suggested that a leptin/ceremide ratio predicted preeclampsia development better than the FDA approved sFlt-1/PLGF ratio.¹²⁵ To-date, studies suggest that leptin plays a role in placental insufficiency through activating mineralocorticoid receptors in the placenta and mediating prohypertensive effects during pregnancy. Rodent studies highlighted the role of leptin in mediating vascular endothelial dysfunction in preeclampsia models. The important clinical question is whether leptin is a promising target to alleviate the syndrome of preeclampsia and potentially stave off preterm labor, reduce mortality risk in mother and fetus and prevent long-term adverse cardiometabolic consequences of preeclampsia pregnancy. The first step to answering these questions has been performed, with the newly published data that leptin can induce hypertension, endothelial and placental dysfunction as well as fetal growth restriction in pregnancy. The next is to establish in preclinical models whether leptin is a key mechanistic contributor to short- and long-term adverse consequences of preeclampsia and the identify the pathways involved. Importantly, ongoing work will determine whether blockade of the leptin receptor may alleviate preeclampsia in pregnancy, or if this avenue proves not clinically applicable, that downstream mechanisms of leptin receptor activation may prove viable targets.

Highlights.

• Leptin is highly associated with preeclampsia and preeclampsia severity independent of BMI in a large number of clinical studies

• Increasing leptin in the circulation of pregnant rodents promotes the development of symptoms of preeclampsia and indicates a crucial role for leptin to induce endothelial dysfunction in pregnancy

• Emerging evidence indicates that leptin promotes placental and endothelial dysfunction via diverse pathways involving endothelin-1, mineralocorticoid receptor activation, angiogenic peptides and mitochondrial dysfunction

• Continued research will uncover whether leptin may be a promising biomarker for preeclampsia and/or provide an avenue for therapy

Abbreviations

ObR

Leptin Receptor

BMI

Body Mass Index

sFlt-1

Soluble FMS-like tyrosine kinase-1

PLGF

Placental Growth Factor

GD

Gestational Day

RUPP

Reduced uterine perfusion pressure

STAT3

Signal Transducer and Activator of Transcription 3

MR

Mineralocorticoid receptor

ENaC

Epithelial sodium channe

NO

Nitric Oxide

ET-1

Endothelin-1

VEGF

Vascular endothelial growth factor

VEGFR

Vascular endothelial growth factor receptor