1. Introduction
Overweight/obesity status has been associated with various chronic conditions, e.g., diabetes, nonalcoholic steatohepatitis, dyslipidemia, hypertension, and heart disease [
1,
2]. Since 1997, the World Health Organization (WHO) has declared overweight/obesity a major public health problem and a global epidemic [
3]. However, the prevalence of overweight/obesity continues to increase among children and adults around the world, including in China [
1,
4,
5]. Increasing evidence suggests that the origins of overweight/obesity in children and adults can be traced back to the first 1000 days from conception to 2 years of age [
2,
6]. Therefore, there has been an increasing focus on preventing overweight/obesity in the earlier stages of life [
7].
Vitamin D (VitD) is a fat-soluble steroid hormone that has a crucial role in calcium and phosphorus homeostasis, bone mineralization, and bone mass acquisition throughout our entire life, especially during childhood [
8,
9]. According to previous studies, skin synthesis with solar activation accounts for 80%–90% of VitD in the human body, while the rest comes from supplements or food [
10]. So far, many studies have reported that VitD deficiency is a risk factor for overweight/obesity [
10], and the potential regulatory mechanisms of VitD deficiency in human adipose tissue include direct adiposity-related gene regulation, and indirect modulation of parathyroid hormone (PTH), calcium, and leptin [
11,
12]. Specifically, VitD binds to VDR exerting endocrine, autocrine, or paracrine actions on the adipose tissue, which will inhibit adipocyte differentiation and reduce fatty acid synthesis, reducing lipid accumulation in vacuoles and inducing apoptosis of maturing preadipocytes [
9,
13]. VitD deficiency can also increase PTH, and then PTH enhances the production of the active VitD metabolite 1,25(OH)
2D, which promotes lipogenesis through increased calcium influx to adipocytes, leading to excess fat and increased body weight [
11,
14]. Additionally, in vitro studies in human adipose tissue samples have shown that vitamin D
3 inhibits leptin secretion [
15], and observational studies support an inverse association between vitamin D and leptin [
16].
So far, most of the studies have focused on the impact of VitD deficiency on overweight/obesity in childhood or school-aged children [
17,
18,
19], and a few have considered the influence of VitD deficiency in pregnancy and its effect on offspring overweight/obesity [
20,
21,
22]. The first year of life is one key stage for preventing obesity; however, studies involving the impact of VitD status on the risk of overweight/obesity in infants remain unclear.
Based on the above, we hypothesize that VitD deficiency similarly increases the risk for overweight/obesity in infants and shows a persistent effect. We recruited six-month-old infants from two community hospitals in Shanghai, China, and followed them up at 12 months to study the association between 25(OH)D concentration and overweight/obesity and to investigate whether there is a suboptimal level of VitD that contributes to overweight/obesity.
4. Discussion
To the best of our knowledge, this prospective cohort study with a relatively large sample size is the first to investigate the relationship between 25(OH)D levels and WLP in infants at 6 and 12 months, and it confirmed that low VitD concentrations increase the risk of overweight/obesity in infants. Moreover, a suboptimal level of 25(OH)D during the first year of life may be relevant for infant overweight/obesity.
In our study, the prevalence of overweight/obesity in infants was 6.88% at 6 months and 5.26% at 12 months. A meta-analysis study in China reported that the overweight and obesity rates in infancy from 1991 to 2015 were 11.7% and 7.0%, respectively [
5]. In a retrospective study from Anhui province, China, the overweight and obesity rates at 6 and 12 months were 7.1% and 6.1%, respectively [
29]. In the Czech, 3.0% and 2.5% of infants were reported to be overweight and obese at 6 months and 12 months between 2008 and 2011 [
30], while in a Canadian study, 6.5% of infants at one year were overweight in 2018 [
31]. The overweight/obesity prevalence in infants has decreased over recent years; however, the current rates are still relatively high. So far, many risk factors contributing to overweight/obesity in early life have been confirmed and included in strategies to prevent overweight/obesity in later life, e.g., parental education, income, mode of delivery, and birth weight [
32], but this has not included VitD status. The impact of VitD status on overweight/obesity in early life needs to be further investigated, as this may optimize the strategies to decrease overweight/obesity rates in both early and later life.
Levels of 25(OH)D and VitD deficiency/insufficiency prevalence tend to vary in infants from different cities or countries. In our study, the median concentrations at 6 and 12 months were 40.6 ng/mL and 42.3 ng/mL, while the prevalence of VitD insufficiency and deficiency was 17.93% and 11.02%, respectively. A previous study conducted in Huzhou city of China reported that the mean 25(OH)D levels at 4–6 months and 7–12 months were 43 ng/mL and 45 ng/mL, and the corresponding prevalence of VitD insufficiency or deficiency in the two age groups was 10.92% and 8.94%, respectively [
33]. In another study from Hong Kong, China, the mean 25(OH)D level at 2–6 months was 23.8 ng/mL, and the frequency of insufficient and deficient VitD status even reached 37.1% [
34]. In a study conducted in Turkey, the mean 25(OH)D concentrations in infants <6 months and 12 months were 28.18 ng/mL and 28.45 ng/mL, respectively; however, 25.5% of infants had an insufficient or deficient VitD status [
35]. Moreover, 25(OH)D concentration <15 ng/mL was considered a deficiency in this Turkish study.
The above studies provide the latest data on VitD status in infancy. Although risk factors for VitD deficiency/insufficiency in infants, such as limited sun exposure, age, and maternal vitamin D status, have been well studied [
34,
36], VitD deficiency/insufficiency in infants is still a common occurrence. Moreover, as one of the important nutrients, VitD deficiency in early life has been implicated in many diseases, such as allergic diseases, growth retardation, and some nervous system disorders [
37,
38,
39]. Hence, VitD status in infancy needs to be given more attention.
VitD status significantly affects infant physical growth, and low VitD status can remarkably increase the risk of overweight/obesity. The weight-for-length Z-score is a predominant standard for assessing overweight/obesity in children younger than 2 years old [
40]. In our study, VitD status was not only significantly related to WLP but also had a strong negative linear relationship with WLP at 6 and 12 months in infants. Moreover, six-month-old infants with 25(OH)D levels <35 ng/mL had a 1.42-fold increased risk of overweight/obesity, while the risk in infants with 25(OH)D levels <35 ng/mL at two time points was higher—2.91-fold. One cross-sectional study carried out in 2021 also found the same relationship, where the increased risk of infancy overweight/obesity was attributed to VitD deficiency; inverse linear relationships were observed between 25(OH)D level and body mass index as well as BMI z-score in one-year-old infants [
35]. In this study, they found that infants with a deficient VitD status had a 2.74-fold increased risk for obesity [
41]. Although there has been limited research on the impact of VitD on infant overweight/obesity, these findings are promising and warrant more investigation, such as extending the follow-up period or developing multicenter trials across cities.
We found 25(OH)D had a threshold effect on overweight/obesity. Currently, the definition of VitD status is based on the Endocrine Society vitamin D guideline [
42]. However, the recommended 25(OH)D levels were defined on the basis of studies focused on bone disease [
42]. In our study, the suboptimal 25(OH)D level of <35 ng/mL for infants at 6 months significantly increased the risk for overweight/obesity at 12 months. There is considerable evidence that school-aged children and adolescents with a 25(OH)D level <20 ng/mL are susceptible to overweight/obesity [
19,
41,
43]. Esmaili et al. pointed out that a higher level of 25(OH)D of 30 ng/mL was a risky inflection point [
18]. Other studies set up suitable VitD levels for overweight/obesity or metabolism disorder in children on the basis of their study population, and inflection values varied, ranging from 10 ng/mL to 32 ng/mL [
44,
45]. In one review, the authors recommended maintaining serum 25(OH)D levels >30 ng/mL in pediatrics to prevent VitD deficiency, thus avoiding the risk of both skeletal and extraskeletal diseases [
46]. Compared to earlier findings, the threshold of 35 ng/mL that we used was higher than that reported before, which may be explained by the high popularity of regular VitD supplementation (98.85%) in Shanghai, which has a high level of medical care. This discrepancy can also be attributed to the younger age of the study population. As it is difficult to agree on a recommended blood level of 25(OH)D, large, well-designed studies should be conducted to evaluate suboptimal 25(OH)D levels in relation to diverse ethnicity, age groups, and diseases.
Potential explanations for the existence of a 25(OH)D threshold with very different effects may be the different growth status of children and concentration-dependent characteristics of 25(OH)D. The effect of 25(OH)D might depend on BMI status. As was reported for 6–18-year-old children, when the BMI z-score was <0, BMI increased with an increasing 25(OH)D concentration, and BMI decreased with the 25(OH)D concentration if the BMI z-score was ≥0 [
47,
48]. Moreover, dual effects of VitD on modulating adipocytes were found in in vitro experiments, where low physiological 1α-25(OH)2D3 concentrations (10
−13 and 10
−11 mol/L) increased fat droplet accumulation, whereas high physiological (10
−9 mol/L) and supraphysiological concentrations (≥10
−7 mol/L) inhibited fat accumulation [
48]. In addition, we speculate that the function of greater 25(OH)D concentration in infancy might be to maintain normal growth rather than having an important role in inhibiting adipose tissue formation or differentiation. Thus, it is plausible that we found a modest association with WLP at 12 months with 25(OH)D concentration over the suboptimal level at 6 months.
One strength of our study is that we focused on the effect of 25(OH)D in infancy on the risk of overweight/obesity. Moreover, we proposed a suboptimal level of 25(OH)D <35 ng/mL during the first year of life as an independent risk factor for infant overweight/obesity.
This study has some limitations. Firstly, our follow-up visit was only up to one year of age; we will continue tracking the long-term effects of VitD status. Secondly, although the rate of loss-to-follow-up was relatively high (23.24%), the rate was still acceptable due to the COVID-19 epidemic crisis. Thirdly, we did not consider some confounders, such as dietary intake and energy expenditure, which may bias our final results. Finally, our study was conducted in infants from Shanghai only, and our results need to be validated or improved in a large-population study involving more cities. Similarly, our findings and the suboptimal 25(OH)D levels varied in relation to genetics, age, and disease, so it is important to be cautious when extrapolating them to other populations or diseases.