Adipokines, hormones produced by adipocytes, exert diverse effects throughout the human body (1). Among these, adiponectin plays a pivotal role in promoting fatty acid oxidation, blunting gluconeogenesis, and mediating various anti-inflammatory effects (2). Adiponectin levels are influenced by gender and BMI, typically ranging between 2–20µg/ml (3). Numerous studies have underscored the significance of adiponectin levels in influencing neonatal outcomes. Yeung et al. reported a significant association between lower quartiles of neonatal adiponectin levels and an increased likelihood of preterm birth (4). Conversely, investigations of the association between maternal adiponectin concentrations and neonatal outcomes have yielded limited results (5, 6).

Irisin, a myokine and adipokine, is responsible for mediating several exercise-related metabolic changes and, potentially, exhibiting antineoplastic effects (7–12). Circulating irisin levels in humans are highly variable (0.01–2000 ng/ml) and influenced by various factors, including exercise, obesity, diet, diseases, and exposure to certain medications (13). Similar to the case of adiponectin, reduced cord blood concentrations of irisin have been associated with lower birthweight, but this correlation is not observed with maternal irisin levels (14). Additionally, diminished plasma irisin is independently linked with increased endothelial microparticles and endothelial progenitor cells, both of which are early markers of endothelial dysfunction, in preterm-born children (15). Conversely, elevated neonatal irisin levels have been linked to an increased risk of fetal macrosomia in a Chinese cohort (16).

It has been hypothesized that vitamin D may exert metabolic effects mediated through its effects on adipokines, including adiponectin (17). In a meta-analysis, Nikooyeh et al. concluded that vitamin D supplementation increases adiponectin concentrations in diabetic patients, hinting at its role as an adiponectin secretagogue (17). Similarly, vitamin D supplementation has been shown to increase irisin concentrations (18, 19), supporting the notion that vitamin D may have a broad effect in the regulation of adipokine secretion.

While total 25-hydroxyvitamin D [25(OH)D] is the most commonly used clinical measure of vitamin D status, debates still persist whether more accurate and clinically impactful measures are available (20). Existing in three forms in the body (21)—free, albumin-bound, and vitamin D binding protein-bound (VDBP)—25(OH)D’s biological activity is hypothesized to be primarily attributed to the free form (22). Hence, the free form could be a more accurate marker of vitamin D status in specific conditions, such as pregnancy (20). Our previous research has revealed a strong positive correlation of maternal VDBP with maternal adiponectin and irisin, while VDBP is associated with adiponectin but not irisin in neonates (23). Furthermore, we have demonstrated a maternal-neonatal relationship with free 25(OH)D levels, although no link to neonatal birth weight or anthropometry was identified (24).

To our knowledge, the associations between free and bioavailable (free with albumin-bound) forms of 25(OH)D with adiponectin and irisin levels have not been investigated. Unraveling these relationships holds the potential to shed light on the nature of vitamin D as a secretagogue of adipokines. Thus, our study aimed to analyze the associations between various forms of vitamin D and adipokine levels in maternal-neonatal pairs from the Mediterranean region.

In this study, we investigated the associations between various forms of 25(OH)D and adipokine levels in maternal-neonatal pairs. Interestingly, we observed a significant inverse association between maternal bioavailable 25(OH)D and neonatal irisin levels, highlighting a potential role of this specific form of vitamin D in regulating neonatal adipokines. We observed no intrarelationships between maternal and neonatal 25(OH)D forms and adipokine levels.

The interplay between vitamin D and adipokines remains a topic of considerable debate. In the general population, vitamin D supplementation generally does not lead to increased adiponectin levels (17). However, subgroup analyses have suggested a positive effect among diabetic individuals and those undergoing daily supplementation (17). To our knowledge, the influence of maternal vitamin D on neonatal adiponectin has not been previously studied, and our findings revealed no association between maternal vitamin D forms and neonatal adiponectin.

Similarly, the connection between vitamin D and irisin is not well-established, with conflicting findings in various studies. For example, Prader–Willi syndrome patients who do not receive vitamin D supplementations have significantly lower irisin levels than those who do (29). In a double-blind, randomized clinical trial, vitamin D supplementation significantly increased irisin serum levels in overweight and obese type 2 diabetics (30). However, serum irisin levels are negatively correlated with 25(OH)D in Charcot-Marie-Tooth patients (31). Similarly, type 1 diabetes mellitus patients demonstrate a similar negative association (32). Other studies have also revealed no association between the two parameters (33). Our study found no association of total and free 25(OH)D with neonatal irisin levels. However, maternal bioavailable 25(OH)D is independently and inversely associated with neonatal irisin concentrations. This observation warrants further investigation, as this study is the first to explore the relationship between maternal vitamin D status and neonatal irisin. The reason why bioavailable 25(OH)D is negatively associated with neonatal irisin concentrations while the free form is not, remains unclear. However, this finding is in accordance with our previous results, where maternal VDBP manifested significant associations with maternal adiponectin and irisin, whereas neonatal VDBP was associated with neonatal adiponectin and irisin, although the later association was not significant. It becomes evident that non-bounds 25(OH)D forms, in this case maternal bioavailable forms, may exert reverse regulatory effects compared to bound forms and VBDP, implying a diverse metabolic role of free and bound vitamin D forms on adipokine concentrations. Further studies are needed to verify our findings and understand the relationship between bioavailable vitamin D forms and irisin.

The impact of irisin levels on neonatal outcomes presents divergent findings in the literature. In our study, we observed a correlation between maternal bioavailable 25(OH)D and reduced neonatal irisin. Some studies have reported that elevated irisin levels are linked to endothelial dysfunction in pre-term children (15). It could be hypothesized that maternal bioavailable 25(OH)D may provide a protective effect against endothelial dysfunction. However, contrasting results have been reported, with other studies indicating an inverse association between irisin levels and the risk of fetal macrosomia (16). The conflicting evidence in existing literature highlights the imperative need for future studies to untangle the intricate role of adipokines, particularly irisin, in neonatal outcomes.

This study has some limitations. A significant constraint is its single-center nature, which potentially limits the generalizability of our findings, i.e. a limited external validity. Variations in 25(OH)D levels due to differences in geographic locations and seasonal changes are well-documented (20). Due to its homogenous population and single location, these factors were not taken into consideration. Furthermore, there are several factors that can influence adipokine levels, such as exercise levels (34), that were not examined in our study. Our observational design also precludes inferring causality from the data. Additionally, the study might be susceptible to statistical type I errors (false positive findings) due to multiple testing. As our statistical analysis plan was however based on hypotheses derived from previous investigations by others, we refrained from adjusting for multiple testing.

In conclusion, our findings indicate that maternal bioavailable 25(OH)D is associated with reduced neonatal irisin concentrations, while total and free maternal 25(OH)D have no impact on neonatal adipokines. Intrarelationships between vitamin D forms and adipokine levels were not observed. The potential protective effects of bioavailable 25(OH)D against harmful irisin effects warrant further investigations. Future studies should explore the underlying mechanisms by which maternal bioavailable 25(OH)D regulates neonatal irisin levels. Additionally, investigating this interplay in diverse populations or at-risk groups like mothers with vitamin D deficiency could provide valuable insights.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Bioethics Committee of Aristotle University in Thessaloniki. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin.

TA: Methodology, Validation, Writing – original draft, Writing – review & editing. HF: Data curation, Visualization, Writing – original draft, Writing – review & editing. HT: Formal analysis, Visualization, Writing – original draft, Writing – review & editing. RC: Data curation, Validation, Writing – original draft, Writing – review & editing. MH: Investigation, Validation, Writing – review & editing. FA: Resources, Validation, Writing – review & editing. SP: Resources, Validation, Writing – review & editing. CA: Resources, Validation, Writing – review & editing. GT: Resources, Validation, Writing – review & editing. CH: Resources, Validation, Writing – review & editing. SK: Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review & editing.