Vitamin D is a fat-soluble nutrient which is mainly obtained from consuming dairy supplements and fish oils. Also, it can be produced endogenously in the skin with exposure to sunlight. To be active, vitamin D must undergo hydroxylation in the liver, being converted to 25-(OH)D, then hydroxylized to the physiologically active 1,25-dihydroxyvitamin D primarily in kidney. This active form is nesessary to promote absorption of calcium in the gut, and enables normal bone mineralization and growth. The newborn disordered skeletal homeostasis, congenital rickets, and fractures is highly considered with severe maternal vitamin D deficiency (34, 35).
The level of vitamin D is affected by many different factors, such as the geographical region, race, weight, gender, lifestyle diet and so on. This group of pregnant women were from north of China and their lifestyle diet are short of vitamin D. The mean serum 25-(OH)D level of the whole group was 14.9 ng/ml, that may be because of not enough vitamin D intake and UVB exposure.
Pregnant women, as a special group of people, are more likely to suffering from vitamin D deficiency, especially for those people who are high-risk pregnancies, such as vegetarians and women with limited sun exposure and insufficient exercise (36-38). Women who have vitamin D deficiency usually do not expereience any clinical symptom, but some may have muscle weakness and weakened bones. The level of vitamin D in newborns is mainly dependent on the level of maternal vitamin D. Consequently, infants of those mothers with or at high risk of vitamin D deficiency are also at risk of vitamin D deficiency (38, 39). Lower maternal vitamin D level is associated with lower bone mineral concentration in newborn infants (40).
Vitamin D and obesity
Obesity is a significant health problem worldwide, particularly in developed nations. Recently, the relationship between obesity and vitamin D drew more and more attention around the world. Some researchers have found that obese people tend to suffer from vitamin D decline or deficiency; consistently, the decrease in the level of vitamin D increases the risk of obesity. Parikh and his co-workers found that the serum level of 25-(OH)D in the obesity group was significantly lower than that in non-obesity group (3). Konradsen et al. reported a significant decrease of both serum 25-(OH)D and 1,25-(OH) D (P<0.001) along with the increasing of BMI. Also, those people with BMI >39.9 kg/m2 had 24% lower level of serum 25-(OH)D and 18% lower level of 1,25-(OH)D than those with BMI <25 kg/m2. The previous reports indicated that relevant evidence was insufficient that high levels of circulating 1,25-(OH)D contribute to the development of obesity (2). Some reports claim that the occurrence rate of vitamin D deficiency increased from 21% to 81% among obese people (3, 41-43). The Fig 2.1 shows that pre-pregnancy BMI negatively correlates with 25-(OH) D level in serum(t=-1.03) and Fig 2.2 indicates the negative correlation between weight gain and maternal 25-(OHD) (t=-0.68). The reason might be that obese people may prefer conservative clothes to cover up their figures and seldom do exercise outside to get enough sun exposure. Furthermore, pregnant women join less outdoors activities, while need more vitamin D, which resulted in the vitamin D deficiency.
Obesity-associated vitamin D insufficiency is likely due to the decreased bioavailability of vitamin D(3) from cutaneous and dietary sources, because of its deposition in body fat compartments (9).
Volumetric dilution can also explain the finding. The researchers gave healthy adults a small dose of vitamin D supplement and did the regression analyses of body size variables against serum 25-(OH)D concentration. They found that obese people need higher loading doses of vitamin D to achieve the same serum 25-(OH)D as normal weight people do. Thus, vitamin D replacement therapy needs to be adjusted by body size, if the desired serum 25-(OH)D concentration is to be achieved (44).On the other hand, the low serum vitamin D level is a risk factor of obesity. A prospective study evaluated 1226 subjects and concluded that vitamin D deficiency is associated with an increased risk of developing obesity (45). Lai et al. found that 25-(OH)D was inversely related to truncal fat mass (P = 0.02) (46).
A study of the relationship between 25-(OH)D and maternal metabolic index indicated that the vitamin D level of the pregnants was generally low. The BMI and the weight gain in the vitamin D deficiency group were significantly higher than those in the vitamin D sufficient group, which suggested the correlation between the low vitamin D level and overweight gain during pregnancy (47).This finding is consistent with current results that the weight gain during pregnancy in the vitamin D insufficient group was less compared to the vitamin D deficient group. A previous clinical trial was done on 2018 described that the overweight and obese women population received vit D supplements compared to the placebo, after 6 weeks high dosage of vitamin D (50,000IU/week) pretreatment ,the means of weight, BMI, waist circumference, and hip circumference decreased significantly (48).
Vitamin D and bone metabolism
Taking optimum dose of vitamin D can not only control the weight gain during pregnancy and lower the risk of obesity complication (48),but also benefit fetal bone growth. Our data showed that newborn’s 25-(OH)D level in the vitamin D insufficient group was higher than that in the vitamin D deficient group, which was also the case in terms of mothers’ 25-(OH)D.
Maternal vitamin D level during pregnancy can program offspring’s skeletal development (49)and body composition in the offspring (50)by influencing the interaction between osteoblasts and adipocytes. Low maternal serum 25-(OH)D level is associated with shorter duration of gestation and, consequently, reduced growth of long bones in newborns (51). In vitamin D-deficient mothers, maternal PTH is elevated, probably due to the increased mineral demands of larger babies (51). Children of mothers with low vitamin D status during late pregnancy had reduced whole-body bone mineral content, bone area, and areal bone mineral density (BMD) at the age of 9 (52). This suggests that vitamin D has an influence on skeletal programming, and the tracking of bone mass lasts throughout childhood. Furthermore, birth weight and growth during the first year of life may contribute to skeletal fragility later in life (53-55).
Previous studies showed that maternal vitamin D status, defined by serum 25-OH-D concentration, is tightly associated with cord blood vitamin D concentration (56-58).
Obesity and bone metabolism
Although obesity has been considered as a condition of low risk for osteoporosis traditionally, this classic view has recently been questioned (59). Bodyweight is directly associated with BMD. A low BMI has been identified as an essential risk factor for lower BMD and predicts greater bone loss in older age (60, 61) and in younger persons in the absence of menses and/or an eating disorder (62). On the other hand, a high body weight can be due to the increased physical activity or obesity, both of which will increase BMD. However, increasing evidence has suggested that excess weight due to adiposity is detrimental to bone and increases fracture risk. In an animal test, short-term and extended high-fat diet-induced obesity caused significant bone loss. Recently, more and more index of bone metabolism has been shown correlated with obesity, such as OC, PTH, P1NP, CTX, and serum calcium.
Reinehr and Roth found that OC levels were lower in obese children and increased when weight loss was achieved (63). OC, also known as bone gamma-carboxyglutamic acid-containing protein, is a non-collagenous protein hormone found in bone and dentin, giving bones strength and flexibility. It is secreted solely by osteoblasts and thought to play a role in metabolic regulation. In addition, it is pro-osteoblastic, or bone-building, by nature (64). It is also implicated in bone mineralization and calcium ion homeostasis. Due to its role in supporting bone strength, the amount of OC increases during periods of rapid growth, notably in children during the first year of life. Therefore, the OC decline will have a negative effect on the bone metabolism. The low OC level in obese people may result from the change of the level of leptin. Leptin is a hormone which is predominantly made by adipose cells that help to regulate energy balance by inhibiting hunger and play a very important role in bone metabolism. Leptin can regulate the OC level in serum. In an animal test, rats with leptin deficiency and leptin resistance had higher OC level. Lepin can also inhibit the production of osteoblasts and the secretion of OC (65). Nevertheless, the OC level of patients in overweight gain group was higher than the normal weight gain group. It might be explained by a feedback mechanism to meet the demand of fetal growth.
PTH, response to the low level of serum calcium, however, the over-responses of PTH will destroy the balance between the bone remodeling and resorbing. Previous publication indicated that the obese people have higher PTH level (66), and Pitroda thought the reason might be the low 25-(OH)D level in the obese people (67). The PTH in the vitamin D insufficient group is clearly lower than that in the vitamin D deficient group. Meanwhile, the PTH in the obese pregnant women were higher than that in the non-obesity pregnant women, and it is also the case in terms of calcium level in serum.
Total procollagen type 1 N-terminal propeptide and C-terminal telopeptides type I collagen
The organic composition of the bone includes mainly typeⅠcollagen (90%), bone binding protein (10%) and trace albumin. Collagen is the crucial component for maintaining the bone integrity. P1NP reflects the change of the newly synthesized typeⅠcollagen, which can be regarded as a symbol of bone remodeling. CTX is the degradation product of the typeⅠcollagen and it is an index of bone resorbing. Some researchers think that the uncontrollable bone resorbing is the main reason leading to the sharply decline of bone mass in obesity (68). Table 3 and 4 showed that the maternal P1NP increased clearly when the weight gain increased during pregnancy and the CTX of the obese pregnant women was higher than that in the normal weight group. The P1NP and CTX were increased to meet the bigger demand of the baby’s bone growth which was indicated by the finding that obese pregnant women have higher probability to deliver a baby whose weight is over 4000 g.