Metabolic Roles of Fatty Acid Binding Protein 4 (FABP4) in Fetal and Maternal Health and Maintenance of Pregnancy in Women with Obesity: A Review.

The concept of metabolic syndrome encompasses a cluster of diseases and organic abnormalities, primarily involving cardiovascular risk factors such as dyslipidemia, hypertension, insulin resistance, and central obesity [ 58 ]. Numerous studies have demonstrated a positive correlation between the presence of these metabolic syndrome components and elevated plasma levels of FABP4, suggesting its potential as a promising biomarker for metabolic risk [ 59 ]. Furthermore, significant evidence links increased plasma FABP4 levels with obesity-related conditions, including polycystic ovary syndrome (PCOS) and diabetes. Given the positive associations between FABP4, obesity markers (such as BMI and body fat levels), and insulin resistance, it is highly plausible that FABP4 is also involved in the pathophysiology of GDM. Moreover, in patients with GDM, high serum levels of FABP4 during the early postpartum period may contribute to a greater risk of developing T2DM and metabolic syndrome in the future [ 60 ]. This protein has also been recognized as a reliable predictive biomarker for cardiovascular diseases owing to its significant role in the proliferation and migration of smooth muscle cells and angiogenesis [ 61 ]. In a 12-year prospective study of 721 individuals (302 men and 419 women), Saito et al concluded that elevated circulating levels of FABP4 can serve as a predictor of cardiovascular mortality in the general population [ 16 ]. In the field of ophthalmology, Ohguro et al found that intraocular levels of free fatty acids and FABP4 were markedly elevated in patients with proliferative diabetic retinopathy and other retinal vascular diseases [ 6 ]. Further evidence of FABP4’s utility as a biomarker was highlighted in a cross-sectional study by Rodríguez-Calvo involving 389 participants. The study indicated that the risk of liver injury, including liver steatosis, and markers of inflammation such as AST, ALT, and GGTP, are positively associated with elevated levels of FABP4 in metabolic patients at heightened cardiometabolic risk, as confirmed by both linear and logistic regression analyses [ 62 ]. Collectively, these studies underscore that elevated plasma FABP4 levels are significantly associated with increased metabolic risk. This connection emphasizes the importance of understanding the underlying mechanisms and solidifies FABP4’s role as a crucial biomarker for predicting future metabolic risk. Currently, due to the potential adverse outcomes for both mother and baby, it is essential to identify biomarkers that can help detect women at an elevated risk of metabolic complications early in pregnancy. Beyond well-established molecules like leptin and adiponectin, newer adipokines such as FABP4 have shown undeniable links to the pathophysiology of GDM [ 60 ]. Recent meta-analyses highlight FABP4 as a particularly promising biomarker for predicting GDM. Early identification of women likely to develop GDM allows for timely intervention and tailored management strategies [ 63 – 65 ]. A study by Francis et al revealed that serum FABP4 levels during early and mid-pregnancy were significantly associated with a higher risk of GDM, compared to a control group of healthy pregnant women [ 66 ]. Similarly, Dong et al demonstrated a correlation between FABP4 levels and insulin resistance in GDM cases [ 65 ]. Elevated FABP4 levels may also serve as biomarkers for other pregnancy complications beyond GDM. In particular, Eastwood et al found that elevated FABP4 levels in the second trimester could predict the risk of hypertension and preeclampsia among women with GDM, with an odds ratio (OR) of 1.15 (95% CI: 1.00–1.27, P =0.045) [ 14 ]. This finding aligns with results from Li et al, which indicated an OR of 1.136 (95% CI: 1.003–1.286, P =0.045) [ 67 ]. These recent studies underscore the potential role of FABP4 in diagnosing metabolic complications during pregnancy, particularly in women with GDM. However, further research is warranted to deepen our understanding and refine the use of FABP4 as a diagnostic tool. In a healthy pregnancy, insulin sensitivity naturally decreases to accommodate the growing fetus’s nutrient needs, allowing for increased glucose production. However, in pregnant women with metabolic disturbances, particularly those with metabolic syndrome and obesity, this balance is often disrupted. In GDM, the primary cause of insulin resistance is insufficient insulin production due to pancreatic β-cell dysfunction [ 20 ]. The immune response shifts significantly during pregnancy to maintain immunological harmony between mother and fetus, though often at a cost. This shift is reflected in elevated levels of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α, in maternal circulation [ 68 ]. FABP4, closely associated with adipocytes within adipose tissue, is particularly responsive during adipocyte differentiation [ 65 ]. It can also be expressed in macrophages, often through the activation of peroxisome proliferator-activated receptor γ (PPARγ) and sirtuin 3 (SIRT3), typically triggered by inflammatory stimuli. In GDM patients, inflammation is generally chronic and low-grade rather than acute [ 65 ]. FABP4 not only mediates PPARγ ligand delivery but also regulates the protein’s level and activation [ 20 ]. Additionally, FABP4 facilitates the ubiquitination and proteasomal degradation of PPARγ. Consequently, preadipocytes lacking FABP4 display enhanced adipogenesis, suggesting that FABP4 modulates insulin responsiveness and adipogenesis by downregulating PPARγ [ 26 ]. Some studies even suggest that FABP4 exhibits insulinotropic potential similar to that of glucagon-like peptide-1 (GLP-1) [ 26 ]. Furthermore, elevated plasma FABP4 levels contribute to insulin resistance by inducing endoplasmic reticulum and oxidative stress [ 69 ]. High levels of FABP4 are often associated with visceral adiposity, including ectopic fat deposition in pancreatic islets, which can indicate an increased susceptibility to elevated insulin secretion in obese patients, particularly in pregnant women, as a means of maintaining glucose homeostasis [ 69 ]. Interestingly, a deficiency of FABP4 in macrophages has been shown to enhance PPARγ activity, which, while simplifying cholesterol efflux, results in reduced cholesterol levels [ 20 ]. Jin et al demonstrated that elevated serum FABP4 levels in early pregnancy could contribute to greater insulin resistance in later trimesters. FABP4 also impairs lipid trafficking and cellular response by altering the adipocytes’ ability to absorb and retain free fatty acids, leading to increased insulin resistance and dyslipidemia, both of which are especially concerning during pregnancy [ 70 ]. Elevated plasma levels of FABP4 can significantly contribute to the severity of various complications during pregnancy. Notably, endothelial dysfunction, linked to increased FABP4 levels, is associated with a higher risk of preeclampsia [ 71 ]. Additionally, a moderately positive correlation has been observed between gestational weight gain and plasma FABP4 levels. In predictive models, FABP4 expression, alongside pre-pregnancy maternal weight and BMI, has emerged as a strong determinant of fetal birth weight [ 72 ]. It is also essential to highlight that women with GDM are at an elevated risk of premature membrane rupture and preterm birth [ 65 ]. A cohort study conducted by Li et al found that patients with elevated plasma FABP4 levels were more likely to develop hypertension and dyslipidemia. These patients were also more likely to require vascular intervention and had more severe peripheral artery disease compared to a control group with lower FABP4 levels [ 73 ]. Similarly, Zhao et al, in a multivariate analysis, confirmed the positive correlation between elevated serum FABP4 levels and the heightened risk of arteriosclerosis, relative to a control group [ 74 ]. However, the relationship between FABP4 levels and cardiovascular risk is complex. Dahlstrom et al found a 2.4-fold higher risk of cardiovascular disease in patients with lower FABP4 levels. These findings highlight discrepancies in previous studies, underscoring the need for further research to clarify the differences [ 75 ]. Additionally, a separate cohort study showed that even first-degree healthy relatives of obese or diabetic individuals had higher serum FABP4 levels than the general population [ 76 ]. In terms of diabetic retinopathy (DR), An et al demonstrated that high FABP4 levels in T2DM patients with mild non-proliferative DR could be predictive of the development of sight-threatening DR [ 77 ].

The global obesity epidemic has escalated significantly in recent decades, with the number of obese individuals worldwide surpassing 1 billion in 2022 [ 1 ]. Maternal obesity is also on the rise, estimated at 20.9% and projected to reach 23.3% by 2030 [ 2 ]. In a healthy pregnancy, a woman’s body undergoes physiological changes to support fetal growth, but metabolic dysregulation can lead to complications affecting both mother and fetus [ 3 ]. Elevated triglycerides, cholesterol, and insulin resistance contribute to obesity, dyslipidemia, GDM, and metabolic syndrome, increasing the risk of cardiovascular disease for both mother and child [ 4 ]. Obesity and GDM, central to this study, are associated with adverse fetal outcomes, including macrosomia, fetal growth restriction, and low gestational age births [ 5 – 7 ]. Obstetric complications such as preterm labor, stillbirth, and higher cesarean rates are also linked to these conditions [ 5 , 8 ]. FABP4 (also known as adipocyte protein 2-aP2 or adipocyte fatty acid binding protein-AFABP) is a fatty acid-binding protein primarily found in adipose tissue and macrophages, involved in lipid metabolism, vascular inflammation, and insulin regulation [ 3 , 4 , 9 ]. Given FABP4’s role in placental lipid transport, understanding its influence on obesity and pregnancy is essential. This article reviews the metabolic roles of fatty acid binding protein 4 (FABP4) in fetal and maternal health and maintenance of pregnancy in women with obesity.

Fetal programming is a well-established paradigm that underscores the profound influence of the intrauterine environment on epigenetic modifications, gene expression, and metabolic signaling pathways [ 92 , 96 ]. During prenatal development, the fetus has heightened susceptibility to maternal and placental factors, which critically shape its physiological trajectory. It is well documented that these mechanisms can predispose offspring to a spectrum of metabolic disorders, including an elevated risk of obesity, type 2 diabetes, and metabolic syndrome. Fetal growth restriction (FGR) frequently arises as a consequence of placental insufficiency, which can stem from maternal complications such as preeclampsia or hypertension, as well as from inadequate maternal nutrition during gestation. This insufficiency is often linked to dysregulated nitric oxide synthesis, leading to compromised vascular endothelial integrity and an increased propensity for hypertension in later life [ 97 ]. Notably, studies have identified a correlation between elevated levels of fatty acid-binding protein 4 (FABP4) and markers of adiposity, suggesting a potential mechanistic link to heightened metabolic disease susceptibility [ 92 , 94 , 96 ]. The long-term ramifications of FGR extend beyond perinatal morbidity and mortality, encompassing an increased risk of adult-onset cardiovascular disease and other chronic conditions [ 93 , 98 ]. Empirical evidence suggests that both intrauterine growth restriction and excessive birth weight independently contribute to a heightened susceptibility to obesity, cardiovascular pathology, and type 2 diabetes in adulthood [ 88 , 92 , 99 ]. Moreover, elevated maternal FABP4 levels have been observed in cases of gestational diabetes, which can predispose offspring to macrosomia and its associated complications [ 7 , 72 ]. In summary, adverse health outcomes in offspring can arise as a consequence of fetal programming or perinatal complications linked to aberrant FABP4 expression, underscoring the intricate interplay between intrauterine conditions and long-term metabolic health.

It is hypothesized that, through its association with inflammatory processes and lipid metabolism, FABP4 plays a role in GDM and other metabolic disorders [ 65 , 100 ], making FABP4 a promising therapeutic target. The potential for FABP4 to serve as a biomarker in predicting GDM risk in pregnant women is under consideration. Studies indicate that women with GDM exhibit significantly elevated serum FABP4 levels compared to healthy women [ 20 , 59 , 65 , 101 , 102 ], with this increase particularly pronounced in the second and third trimesters of pregnancy [ 103 ]. However, these are currently theoretical concepts, which would require the development of methods to measure FABP4 in larger cohort studies before practical application. Defining precise FABP4 threshold values that correlate with specific pathological states would also be essential [ 23 , 64 ]. Beyond the mother’s metabolic disorders, the impact of FABP4 on placental and fetal development should also be explored. Further studies could clarify whether FABP4 might also be predictive of long-term metabolic complications in offspring ( Figure 2 ) [ 23 , 104 ]. Various approaches to modulate FABP4 levels through pharmacological and non-pharmacological means are currently under investigation. Among the pharmacological methods, the most promising is the use of FABP4 inhibitors, such as BMS309403, which block the binding of FABP4 to fatty acids [ 105 ]. Studies in animal models have shown that BMS309403 can reduce blood glucose levels and improve lipid metabolism, thereby alleviating diabetic symptoms. Additionally, the therapy led to a decrease in pro-inflammatory cytokines, including TNF-α and IL-6, suggesting an anti-inflammatory benefit of BMS309403 [ 20 , 65 , 106 ]. In a study involving mice on a high-fat diet, BMS309403 administration resulted in up to a 50% reduction in atherosclerosis symptoms, indicating potential for treating other metabolic disorders like atherosclerosis [ 93 , 94 ]. Unfortunately, despite its efficacy, adverse effects associated with BMS309403 therapy have been observed, including impaired cardiac contractility, which presents a major limitation and risk in its use. Thus, further studies are needed to assess the safety of long-term use, especially in pregnant women and individuals with cardiovascular diseases [ 107 ]. A non-pharmacological approach to modulating FABP4 levels includes dietary interventions. In one study, the administration of omega-3 fatty acid ethyl esters over 4 weeks significantly reduced FABP4 levels in dyslipidemic patients. The acids included EPA and DHA, and it is speculated that this reduction in FABP4 expression was due to decreased expression of the PPARγ2 and C/EBPα genes, which regulate adipocyte differentiation [ 83 ]. This line of research offers an innovative non-pharmacological strategy for regulating FABP4 levels, potentially avoiding the adverse effects associated with pharmacological inhibitors like BMS309403 [ 107 ]. A primary focus for future research may be elucidating the mechanisms of FABP4 action across various pathological states, especially during pregnancy. Our current understanding of the specific tissues contributing to elevated FABP4 levels during pregnancy remains notably limited. Additionally, it is crucial to thoroughly investigate how the complex hormonal changes occurring in a pregnant woman’s body influence FABP4 expression. Given these uncertainties, it remains unclear whether elevated FABP4 levels are causative or a consequence of metabolic disorders, such as GDM [ 102 ]. Notably, many studies have relied on animal models, with limited data on the impact of these therapies in humans. Thus, further clinical studies are essential to evaluate the safety and efficacy of these therapies in pregnant women, as well as their potential impact on the fetus [ 23 , 65 ]. Research on FABP4 as a potential biomarker for GDM must also be expanded to assess its clinical relevance through larger cohort studies. Currently, no standardized FABP4 threshold values exist for diagnosing GDM or other metabolic syndromes influenced by FABP4 [ 64 ]. Investigating whether FABP4 levels could predict other pregnancy complications, such as preeclampsia, would be important for the diagnosis and treatment of these conditions, which often carry long-term health implications for both mother and child [ 108 , 109 ]. A promising direction for future investigation is the development of therapies aimed at modulating FABP4 levels. FABP4 inhibitors, such as BMS309403, have shown initial efficacy in animal models [ 65 ]. However, further clinical trials are necessary to evaluate these therapies’ efficacy and safety in humans, particularly concerning long-term maternal and fetal health effects. As early reports indicate cardiovascular adverse effects with these therapies, it is vital to assess their suitability for use during pregnancy, especially given the sensitive nature of this period [ 94 ]. Moreover, non-pharmacological strategies for FABP4 modulation require further exploration. There is evidence that administering omega-3 fatty acids, including EPA and DHA, can reduce FABP4 levels in dyslipidemic patients, suggesting dietary interventions as an effective means of regulating FABP4. Future research should assess the safety and efficacy of this approach specifically in pregnant women [ 83 ].

Our analysis shows the critical role of FABP4 in regulating metabolic processes in pregnant women with obesity. FABP4 is essential for intracellular fatty acid transport, participating in lipid oxidation and fat storage in adipocytes. Research indicates that excess body fat and inflammation contribute to elevated serum FABP4 concentrations in women with higher BMI. Due to its functions, FABP4 is gaining attention as a potential biomarker for predicting metabolic complications in obese pregnant women. Its serum levels could serve as an early indicator of patients at risk for gestational diabetes and pregnancy-induced hypertension, enabling early intervention to reduce risk and improve health outcomes for both mother and child. The therapeutic potential of FABP4 in managing obesity-related pregnancy complications is also under investigation. Pharmacotherapy targeting FABP4 reduction is being considered, with promising benefits for enhancing insulin sensitivity, reducing inflammation, and modulating lipid metabolism. FABP4 inhibitors, such as BMS309403, have shown encouraging results, improving glucose balance and reducing hypertension risk. Additionally, dietary interventions, such as omega-3 fatty acid ethyl esters (eg, EPA and DHA), may complement therapy by preventing metabolic complications and supporting fetal health. Further research into FABP4 would deepen our understanding of its mechanisms and support the development of effective therapeutic strategies. Utilizing FABP4 as a biomarker and therapeutic target could substantially enhance healthcare quality for pregnant women, improving prevention of complications and optimizing pregnancy outcomes.