Vitamin D deficiency and childhood obesity: interactions, implications, and recommendations
Nutrition and Dietary Supplements, February 2015 Volume 2015:7 Pages 29—39, DOI http://dx.doi.org/10.2147/NDS.S52024
Peterson CA, Department of Nutrition and Exercise Physiology, University of Missouri-Columbia, Columbia, MO, USA
Abstract: Vitamin D deficiency and childhood obesity have been classified as epidemics throughout the world, and both share some common risk factors including poor diet and inactivity. Observational and clinical studies show that vitamin D status and fat mass are inversely correlated. It is not clear whether vitamin D deficiency contributes to, or is a consequence of obesity, or whether there are regulatory interactions between excess adiposity and vitamin D activity. The effects of this deficiency in childhood obesity appear to have negative influences on overall health, including insulin resistance, inflammation, and impeded bone mineralization, as well as increased future risk of type 2 diabetes, cardiovascular disease, and osteoporosis. The rather ubiquitous distribution of the vitamin D receptor and the 25-hydroxyvitamin D 1 a-hydroxylase throughout the body, including evidence for a role of vitamin D in adipogenesis and adipocyte metabolism, may in part explain these widespread effects. Most of the findings to date suggest that the vitamin D needs of obese children are greater than the nonobese. Although ultraviolet B-induced skin synthesis is a main source of vitamin D, its use is neither feasible nor prudent due to limited sun availability for many and concerns for skin cancer. Likewise, obtaining adequate vitamin D from natural food sources alone is generally not achievable, and even in countries that allow fortification, vitamin D intakes are low. Therefore, in obese children, vitamin D supplementation is warranted. Weight loss interventions using energy restriction and physical activity may also improve the poor vitamin D status associated with obesity. More research is needed to define optimal vitamin D status in this vulnerable population, including investigations to determine the efficacy of vitamin D supplementation in attenuating the conditions associated with childhood obesity, and to further elucidate the mechanisms by which vitamin D exerts its effects on health.
Some notes from the purblication
Obesity strongly associated with low vitamin D
Obese with lowest vitamin D levels gained more weight
Obese need larger doses of vitamin D to achieve same blood level
Many other health problems occur if vitamin D levels are not restored
See also VitaminDWiki
- Overweight and obese lost 12 lbs with vitamin D in 6 months– RCT May 2015 adults
- Obese need 2X to 3X more vitamin D - Nov 2014 adults
- Obese of all ages have lower levels of vitamin D – meta-analysis May 2015
- Antibiotics and Vitamin D are associated with many of the same diseases contains the following
Strong indications in Missing Microbes that early antibiotics increases the risk of obesity
- Farmers have been giving low-level anitbiotics to animals since they learned long ago that it would increase by 10% the animal weight without increased cost of feed
- Mice given low-level antibiotics for first 4 weeks of life become heavier later in life
- Children who are given antibiotics in first 6 months of life are 5X more likely to become obese (study in England of 14,000 births)
- US States which get the most antibiotics are those states with the most obesity (CDC)
- Obese US adults have 1/2 of the gut biotic diversity of non-obese adults (400,000 vs 800,000)
- Germ-Free mice became obese when given fecal transplants from mice who had antibiotics and became obese
This is a strong indication that the cause of the obesity was the gut microbiome
Overview Obesity and Vitamin D contains the following summary
- FACT: People who are obese have less vitamin D in their blood
- FACT: Obese need a higher dose of vitamin D to get to the same level of vit D
- FACT: When obese people lose weight the vitamin D level in their blood increases
- FACT: Adding Calcium, perhaps in the form of fortified milk, often reduces weight
- FACT: 140 trials for vitamin D intervention of obesity as of Sept 2019
- FACT: Less weight gain by senior women with > 30 ng of vitamin D
- FACT: Dieters lost additional 5 lbs if vitamin D supplementation got them above 32 ng - RCT
- FACT: Those with darker skins were more likely to be obese Sept 2014
- SUGGESTION: Probably need more than 4,000 IU to lose weight if very low on vitamin D due to
risk factors such as overweight, age, dark skin, live far from equator,shut-in, etc.
- Obesity category has
VitaminDWiki pages in BOTH the categories Infant-child and Obesity
- Obesity 3X more likely in US children having low vitamin D – July 2019
- Overweight children are 3.4 X more likely to have low Vitamin D – March 2019
- Indoor pollution is a problem with obese black asthmatic children – May 2018
- Severe Non-Alcoholic fatty liver disease treated by Omega-3 – RCT April 2018
- The Convergence of Two Epidemics: Vitamin D Deficiency in Obese School-aged Children – Jan 2018
- Fatty liver disease in children nicely treated by combination of Vitamin D and Omega-3 – RCT Dec 2016
- Omega-3 in infancy reduces Obesity following antibiotic (confirmed in rats, suspected in humans) – Feb 2016
- Vitamin D deficiency and childhood obesity: interactions, implications, and recommendations (5,000 IU) – Feb 2016
- Obese children – 71 percent had low vitamin D– Jan 2016
- Infant risk of obesity increased by 50 percent if low vitamin D during pregnancy – Sept 2015
- Obese children need more vitamin D – Review Feb 2015
- Overweight children associated with low vitamin D during pregnancy – 2015, 2018
- Higher vitamin D at birth associated with less diabetes and obesity 35 years later – Jan 2014
- More Hypertension in obese children with low vitamin D, especially at night – Dec 2013
- Very poor follow-thu with vitamin D testing and supplementation of obese children – June 2013
- Obese children gain weight more quickly when have low vitamin D – Oct 2013
- Obese mothers with adequate vitamin D gave birth to low D and fat infants – Jan 2013
- Heavier kids more vitamin D deficient, especially if dark skinned – Pediatrics Dec 2012
- Obese children with celiac disease had lower levels of vitamin D – April 2012
- The more vitamin D the lower the infant BMI – March 2011
- Obama task force told that childhood Obesity linked to Vitamin D Deficiency – Aug 2010
VitaminDWiki pages in BOTH the categories Youth and Obesity
- Overweight children are 3.4 X more likely to have low Vitamin D – March 2019
- Half of obese black teens achieved at least 30 ng of Vitamin D with 5,000 IU daily – June 2018
- The Convergence of Two Epidemics: Vitamin D Deficiency in Obese School-aged Children – Jan 2018
- Obese children – 71 percent had low vitamin D– Jan 2016
- 5,000 IU daily or 50,000 IU Vitamin D weekly repleted many dark skinned adolescents – RCT Dec 2015
- Obese children need more vitamin D – Review Feb 2015
- Obese teens need more than 2,000 IU of vitamin D for 3 months– RCT Feb 2015
- Vitamin D deficiency 4X more likely in Italian teens if: dark skin, winter, obese, little sun, or use sunscreen – June 2014
- Increasing time with indoor media, prescribe time outdoors - Sept 2013
- Italian youth vitamin D deficiency increased likelihood: 27X if winter, 5X if obese, etc. – Aug 2013
- 3X more abdominal obesity among Korean children having low vitamin D – July 2012
- Korean teens more likely to be obese if have less than 18 ng of vitamin D – June 2012
- Bariatric surgery less than 30 ng of vitamin D – 82 pcnt teens, 100 pcnt of black teens – June 2012
- Teen obesity strongly associated with vitamin D deficiency – April 2012
- Obesity lowers vitamin D which increases probability of diabetes in children – Nov 2011
- Obese teens needed 4000 IU of vitamin D - Nov 2011
- Obese children had low vitamin D – fat under dark skin – fat in white body – Mar 2011
- Increased forearm fractures in obese children - Nov 2010
- Perhaps low vitamin D increases child obesity - Sept 2010
- Obesity in American-Indians and African-American teens
- Low vitamin D in teens: especially black or overweight – June 2010
- Calcium deficiency is a risk factor for overweight female teenagers April 2010
Table of contents
- Vitamin D: the hormone, the nutrient, and its action
- Vitamin D deficiency: reemergence, diagnosis, and prevalence in children
- Interactions and implications of vitamin D deficiency in obese children
- Conditions in obese children affected by vitamin D status
- Adipose-endocrine response as an important link between vitamin D deficiency and obesity-related conditions
- Age and pubertal status confound the association between vitamin D and childhood obesity
- Effects of vitamin D status on weight loss and vice versa
- Recommendations for treating vitamin D deficiency in obese children
- Meeting vitamin D needs through sun, food, or supplement sources
Childhood obesity is a major global health crisis. A systematic analysis of 1,769 reports representing 188 countries reveals that the worldwide prevalence of childhood overweight and obesity rose by nearly 50% over a span of three decades.1 Roughly 43 million children are estimated to be overweight or obese throughout the world, and another 92 million are at risk of overweight.2 If this trend continues, the global prevalence of childhood obesity is predicted to reach 60 million by 2020.2
The implications of this crisis are numerous and far reaching, involving both the individual and society.3 For a child, there are physical health and psychosocial and functional consequences across a lifetime as studies show that childhood obesity is accompanied by an increase in associated chronic conditions such as insulin resistance (IR),
Although classified as a nutrient (largely due to the timing of its discovery which coincided with the discovery of other fat-soluble vitamins), vitamin D is more fittingly described as a prohormone/hormone.9 It exists in two forms: vitamin D2 and vitamin D3. Vitamin D2, or ergocalciferol, is a photoproduct of the irradiation of ergosterol, a fungal sterol also known as provitamin D2. Vitamin D3, or cholecalciferol, is produced following the irradiation of provitamin D3 (7-dehydrocholestrol) in the epidermis and dermis layers of the skin.10 The term “vitamin D” without a subscript refers to vitamin D2, vitamin D3, or both. The primary source of vitamin D is from skin synthesis as there are few naturally occurring dietary sources.11
Both vitamin D2 and vitamin D3 are hydroxylated twice to become active and capable of binding to their vitamin D receptor (VDR). The first hydroxylation occurs in the liver via 25-hydroxylase, forming 25-hydroxyvitamin D (25(OH)D) (also known as calcidiol). This is the major circulating form of vitamin D and is the primary determinant of vitamin D status. The enzyme 25-hydroxyvitamin D 1a-hydroxylase (1a-OH-ase) converts 25(OH)D to its active form, 1,25- dihydroxyvitamin D (1,25(OH)2D, also known as calcitriol). Although this enzyme is classically identified in the proximal tubules of the kidney, 1a-OH-ase (CYP27B1) gene expression has been demonstrated in a wide range of extrarenal tissues, including, but not limited to, immune, brain, pancreatic, and adipose tissue.12,13 Renal activation of 25(OH)D results in elevated levels of circulating 1,25(OH)2D, which subsequently binds to the VDR in target tissues. Extrarenal formation of 1,25(OH)2D appears to act locally by binding to VDR present within the same or neighboring cells. These intracrine and autocrine/paracrine actions are thought to be regulated by cytokines and to be responsible for the effects of 1,25(OH)2D on cell proliferation, differentiation, and apoptosis.14
Vitamin D and its metabolites are transported bound to and solubilized by plasma protein carriers. Vitamin D-binding protein (DBP), a protein primarily produced by hepatic parenchymal cells, is the major transport protein. It binds 85% of circulating 25(OH)D, while albumin and lipoproteins account for the remaining 15%.15
Once synthesized, from renal or local production, 1,25(OH)2D is transported to nuclear VDR in target cells.16 The human VDR plays a central role in the biological actions of vitamin D as it regulates the expression of numerous genes in a largely ligand-dependent manner.16 VDRs, upon activation by 1,25(OH)2D, form a heterodimer with retinoid X receptors (RXRs). These VDR-RXR heterodimers bind to vitamin D response elements of multiple genes, which results in either the transactivation or repression of these genes.17
Throughout childhood, vitamin D plays important roles in calcium and phosphorus homeostasis and bone growth/ mineralization. Vitamin D deficiency in childhood causes osteomalacia, leading to growth retardation and skeletal deformities (ie, rickets).10 More common, however, is an insidious presentation of vitamin D deficiency, which may prevent children and adolescents from reaching peak bone mass and predicted height.18
There is evidence that vitamin D is necessary for many other cellular processes. In addition to the organs responsible for calcium/phosphate homeostasis, VDRs are expressed in a variety of tissues and cells such as the hepatocytes, myocytes, adipocytes, pancreatic P-cells, and several immune cells, all of which are associated with obesity and its associated metabolic complications.16,19,20
Rickets, first documented in approximately 120 AD by Sorano of Ephesus, is the most recognized disease of vitamin D deficiency as it has plagued humans throughout history.21 It became especially problematic in Europe and North America during the Industrial Revolution with the related reduction in sun exposure for those living and working in urban environments. Advancements in the science of vitamin D in the mid-20th century led to public health initiatives such as food fortification, which eliminated rickets as a significant health problem in the countries that implemented them.7 However, in the last 10-15 years, evidence has surfaced for a reemergence of rickets in certain ethnic and minority groups in Europe and Australasia and an alarming prevalence of poor vitamin D status worldwide.22 The factors speculated to contribute to this rise in vitamin D deficiency include lower intakes of vitamin D-fortified foods, use of sunscreens/blocks, reduced time spent in outdoor activities, and air pollution.23 Moreover, our understanding of the role of vitamin D in human health has expanded into areas beyond bone and has subsequently put into question the definition of adequate vitamin D status.23’24
The best available indicator of vitamin D status is the serum concentration of 25(OH)D,25 although the extent to which this measurement relates to or serves as a predictor of health outcomes has not been fully elucidated. Furthermore, there is no general agreement on the required serum 25(OH)D for adequate status. For example, the Institute of Medicine (IOM) defines vitamin D deficiency, or hypovitaminosis D, as a serum 25(OH)D concentration <50 nmol/L (20 ng/mL),26 whereas the Endocrine Society has suggested that a 25(OH)D concentration between 75 nmol/L and 250 nmol/L (30100 ng/mL) is required for sufficiency, with the intermediate concentration range of 52-72 nmol/L (21-29 ng/mL) classified as “insufficient”.27 Vitamin D status classifications within pediatric clinical practice guidelines are similarly controversial. The American Academy of Pediatrics (AAP)28 cut-off values are identical to IOM with a 25(OH)D concentration >50.0 nmol/L considered to be “sufficient”, while the Society for Adolescent Health and Medicine (SAHM)29 considers a 25(OH)D serum concentration between 75-125 nmol/L (30-50 ng/mL) to be “sufficient” for the adolescent.
Hypovitaminosis D is a significant problem among people of all ages around the world,30 although there are large gaps of information on the pediatric populations of some countries.31 The estimated worldwide prevalence of hypovitaminosis D in children and adolescents is rather wide, between 29% and 100%,32 and surveys show it to be in part related to the degree of adiposity, with
- healthy weight at 21%,
- overweight at 29%,
- obese at 34%, and
- severely obese at 49%.33
Thus, obese children are a particularly vulnerable group for poor vitamin D status, which in turn appears to exacerbate the effects of obesity alone on overall health.31,33,34
It is not clear whether hypovitaminosis D contributes to, or is a consequence of, obesity, or whether there are regulatory interactions between excess adiposity and vitamin D activity. Data from a prospective, population-based study following 1,226 adult participants over a decade showed that the odds of gaining more than 3.7 kg (75th percentile) between the second and third visits in those with 25(OH)D serum concentrations <42 nmol/L (17 ng/mL) was 2.37 times greater than those with higher 25(OH)D concentrations.35 This suggests that the poor vitamin D status in the obese may not be secondary to obesity but may instead precede it. In support of this, a population-based longitudinal study of children in the Brazilian Amazon found the effect of the obesity- associated gene variation (FTO rs9939609) to be more pronounced among children with insufficient vitamin D status.36 Conversely, a recent bidirectional Mendelian randomization analysis of multiple cohorts involving a total of more than 42,000 individuals provided evidence of obesity as a causal factor in the development of vitamin D deficiency but not vice versa.37 This analysis revealed that the “body mass index (BMI) allele score” created by the investigators was associated with both BMI and 25(OH)D concentration among study participants, and each 10% increase in BMI leads to a 4.2% decrease in 25(OH)D concentration.37 However, although both of the two “25(OH)D allele scores” were linked with serum 25(OH)D concentration, neither was associated with BMI.
IR and inflammation are commonly seen in overweight/obese children and are predictive of the development of metabolic syndrome, type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and perhaps osteopenia/osteoporosis. For example, reports indicate that children with these two risk factors are significantly more likely to have T2DM and CVD 25-30 years later compared with their peers.38,39
The relationship between poor vitamin D status and IR, T2DM, and metabolic syndrome is the most well studied and was first observed in obese adults.40 Similar observations have since been made in obese children. Most, although not all, show significant associations between circulating 25(OH)D concentration and indices of IR and blood glucose control; their findings have been covered in detail elsewhere.41 The very few published intervention trials using vitamin D supplementation to improve IR and impaired glucose tolerance in obese children or adolescents have yielded beneficial effects.41 For example, results from our 6-month randomized controlled trial (RCT) of obese adolescents (age =14.1±2.8 years; BMI =39.8±6.1 kg/m2) supplemented with 4,000 IU per day showed an attenuation of IR similar to results involving the use of the drug metformin.42 By comparison, the results of a 2012 meta-analysis of the evidence on vitamin D supplementation and glycemic control in adults revealed a weak effect of vitamin D supplementation in reducing fasting glucose and improving IR in patients with T2DM or impaired glucose tolerance.43 Much of this discrepancy can be attributed to differences in methods employed, such as vitamin D dose and outcome measures, and participant characteristics, most notably body weight/ fat status, initial vitamin D status, and age. Further, it is speculated that the status of both vitamin D and parathyroid hormone (PTH) needs to be considered in evaluating the impact of vitamin D status on glucose metabolism.44 More RCTs are warranted.
The biological mechanisms by which vitamin D influences glycemic control in obesity have yet to be determined but are thought to involve enhancement of peripheral/hepatic uptake of glucose, attenuation of inflammation, and/or regulation of insulin synthesis/secretion by pancreatic P-cells.41 Moreover, data from one of the first reports to examine the association between vitamin D deficiency and IR in obese children indicated that the most clinically meaningful threshold of serum 25(OH)D concentration for the identification of IR and impaired glucose homeostasis in the obese is 50 nmol/L (20 ng/mL).45 This is the cut-off used by the IOM in the definition of vitamin D deficiency.
A new systematic review of 35 studies evaluated the degree to which vitamin D and CVD risk factors are associated in obese children.46 The cross-sectional studies included in the analysis showed a relationship between 25(OH)D and systolic blood pressure but not the prospective studies. The lone RCT in the review suggested a relationship between vitamin D status and arterial stiffness. There were no associations between 25(OH)D and diastolic blood pressure or low-density lipoprotein cholesterol, and the links with high-density lipoprotein cholesterol and triglycerides were capricious.
Anther condition related to childhood obesity and metabolic disturbances is nonalcoholic fatty liver disease (NAFLD). Since both NAFLD and serum 25(OH)D concentration are associated with adiposity and IR, interest in examining their potential pathogenic link has emerged.
Pediatric NAFLD is a condition characterized by hepatic fat infiltration >5% hepatocytes, as assessed by liver biopsy, in the absence of viral, autoimmune, and drug-/alcohol-induced liver disease.47 It is becoming one of the most common complications of childhood obesity and is strongly associated with the clinical features of IR, especially the metabolic syndrome and T2DM.47 Two separate observational studies showed that compared with non-NAFLD obese children and teens, those with NAFLD had significantly lower serum concentrations of 25(OH)D, which was correlated with IR in those with NAFLD but not in those without NAFLD.48’49 Another investigation showed that lower 25(OH)D concentration is associated with NAFLD, independent of adiposity, physical activity, and IR.50 At odds with these findings, an earlier report using data on 1,630 children, aged 12-19 years, from the National Health and Examination Survey (NHANES) 2001-2004, found vitamin D status not to be independently associated with NAFLD.51 It remains to be determined whether poor vitamin D status contributes directly to the risk of developing NAFLD or if this association is confounded by hepatosteatosis,48 as the liver is a primary site of vitamin D activation.
The bone mass attained during growth is a critical determinant of the risk of osteoporosis later in life.52 Those with higher peak bone mass after adolescence have a protective advantage during normal aging and menopause when significant bone loss occurs. Although it is known that peak bone mass is determined by genetics and lifestyle factors, the effects of obesity on bone mineral accretion are not fully discerned. In contrast with adults in whom overweight/obesity is protective to bones, there is evidence that obesity in children is a risk factor for low bone mass and fractures.53 However, this phenomenon is not uniformly observed.54 Efforts of new investigations have focused on addressing the reasons for the discrepancy, including distribution of body fat (abdominal obesity),55 and/or the presence of comorbidities, such as IR,56 metabolic syndrome,57 and NAFLD.58
Factors thought to be responsible for the altered bone mass described in childhood obesity include changes in the hormonal milieu (eg, increased conversion of androstenedione to estrogen),59 and the participation of adipokines (resistin, adiponectin, leptin, osteocalcin)60 and adipose-derived inflammatory markers (interleukin-6 [IL-6] and tumor necrosis factor-a [TNF-a]) in bone remodeling.58,61 Another likely contributor is the poor vitamin D status related to obesity, via its indirect (inflammation) and/or direct (calcium homeostasis/bone mineralization) skeletal effects.
Children have high demands for dietary calcium to support the mineralization of growing bone. It is well established that serum PTH concentration varies inversely with absorbed calcium and serum 25(OH)D concentration. It has been proposed that the point along the 25(OH)D continuum at which PTH becomes constant is an indication of the point at which calcium absorption becomes constant.62 A study of young, healthy children in Canada demonstrated that a 25(OH)D concentration of 100 nmol/L was required to see a plateau in PTH.63
The effect of excess body fat is theorized to 1) increase the metabolic clearance of vitamin D and its metabolites through enhanced uptake, 2) decrease the bioavailability of vitamin D once deposited in adipocytes, and/or 3) create a volumetric dilution of vitamin D due to a larger body mass.64,65 For comparison, the amount of total body fat mass of lean children (BMI for age # 15th percentile) is described to be between 1.8 kg and 2.2 kg, 2.7 kg and 4.2 kg, and 6 kg and 10 kg, for children 3-5 years, 6-11 years, and 12-19 years of age, respectively, while the total body fat mass of overweight/ obese children (BMI for age $ 85th percentile) of similar age is reported to be more than threefold greater.66 Adipose tissue, the storage site of this excess body fat, was once thought to be inert but is now regarded as a highly metabolic endocrine organ.67 It secretes more than 260 different proteins/peptides (adipokines, chemokines, cytokines) and is a major player in glycemic control.68,69 Vitamin D appears to have a role in adipose tissue and its metabolic processes; however, the molecular basis of the interactions of 25(OH)D, 1,25(OH)2D, DBP, and VDR after sequestration in adipose tissue and their regulations are not well understood.
The genes for VDR and vitamin D-metabolizing enzymes (CYP27A1, CYP27B1) have been identified in both animal and human adipocytes.19,70 Research demonstrates that both the active form, 1,25(OH)2D, and the parent molecule, vitamin D3, influence several key adipogenic genes and transcription factors as well as lipid accumulation.19,70 Yet, the specific function of vitamin D in the adipogenic process remains largely ambiguous, and often contradictory, with studies showing both stimulation and inhibition of adipogenesis.67
Vitamin D metabolites also influence adipokine production and the inflammatory response in adipose tissue.67 There is convincing support for chronic inflammation as the causal link between obesity and its related metabolic conditions, such as IR, liver fat deposition, and poor bone mineralization. As adipocytes expand, they produce and secrete several inflammatory cytokines and chemokines such as TNF-a, IL-6, monocyte chemotactic protein-1, and leptin.67 Observational studies have shown an inverse correlation between 25(OH)D concentration and several of these inflammatory cytokines.71,72 Furthermore, multiple in vivo and in vitro studies have reported that 25(OH)D downregulates the production and secretion of multiple pro-inflammatory cytokines including IL-1, IL-2, IL-6, IL-12, C-reactive protein, TNF-a, and interferon-y.73,74
From the literature on vitamin D and childhood obesity, age and pubertal status surface as significant confounders. A recent study of obese 2- to 6-year olds found an inverse relationship between child age and serum 25(OH)D concentration,75 while another in older children reported the same finding.76 Greater vitamin D intakes in younger children may provide an explanation. Data collected from NHANES 2003-2003 show that 76% and 78% of 1- to 3-year-old boys and girls, respectively, have total intakes (diet and supplements) above the IOM recommendations, while, in 14- to 18-year-old boys and girls, only 32% and 54%, respectively, have intakes above recommendations.77 Greater sun exposure in younger children is another feasible explanation as they engage in more outdoor playtime than older children and adolescents.78,79
Excess adiposity during childhood may advance puberty in girls and delay puberty in boys.80 Puberty is known to affect many of the metabolic conditions associated with obesity and vice versa. IR and compensatory hyperinsulinemia may represent a common thread contributing to many of the pubertal changes reported to occur with childhood obesity81,82 Two studies designed to specifically examine the effects of puberty on the association between 25(OH)D serum concentration and IR show that it does not become significant until children reach puberty.83,84 Further, an analysis of cross-sectional data of obese children required adjustments for puberty to reveal associations between vitamin D status and homeostatic model assessment - insulin resistance (HOMA-IR),85 and the aforementioned report of very young obese children found no association between vitamin D status and IR.75
Preliminary results in obese adults hinted at a more favorable response (greater body fat loss) to energy restriction in those with adequate vitamin D status.86 However, a 2014 meta-analysis of RCTs using vitamin D supplementation without imposing energy restriction revealed only a small effect of improved vitamin D status on BMI but not fat mass.87 Interestingly, this meta-analysis also indicated that studies in older people and men were less likely to show an effect on BMI or fat mass. There is a paucity of data available on the effect of vitamin D supplementation on weight loss in children. In one study of overweight children undergoing diet counseling, high milk consumption (primary source of vitamin D in the USA) did not lead to greater weight loss but attenuated insulin action.88 (Unfortunately, serum 25(OH)D was not measured, so associations with vitamin D status could not be assessed.) Likewise, in our RCT of obese adolescents also undergoing diet counseling, although vitamin D supplementation decreased IR, neither body weight or waist circumference changed over 6 months.42 Of relevance, an earlier RCT of healthy girls, 10-17 years of age, found that premenarcheal participants given weekly oral doses of vitamin D for 1 year had significant increases in lean body mass and height, with no changes in body weight, suggesting a decrease in body fat (although not reported).89 Despite these data, however, the overall evidence of positive effects of vitamin D on weight or fat loss is thus far underwhelming.
Reports have looked at the effect of weight loss on vitamin D status. In a cross-sectional study of obese children who achieved a reduction in overweight over a 1-year time period, serum PTH decreased, and serum 25(OH)D increased significantly compared to obese children without weight loss.90 Similar observations have been described in adult weight loss studies.91,92
The IOM-recommended dietary allowance is 600 IU (15 |ag) daily for children 1-18 years of age.26 Recommendations of pediatric medical societies such as the AAP or the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition are below this dose,93,94 while the Endocrine Society and SAHM guidelines suggest that this same age group may need up to 1,000 IU (15-25 q.g) per day (Table 1).27,29 This disagreement reflects different goals and views on current evidence.95
The above recommendations are generally intended for healthy populations and do not reflect the unique needs of disease groups or of those with diagnosed vitamin D deficiency.
With the high prevalence of hypovitaminosis D among obese children, the requirements for most obese youth would likely fall under a different set of recommendations. For children with documented deficiency (serum 25(OH)D <37.5 nmol/L [15 ng/mL]), the AAP recommends 5,000 IU (124 |ug) per day until stores are replenished.28 Findings from our study of obese adolescents support this higher dose. After 3 months of supplementation with 4,000 IU (100 pg), none of the participants were of vitamin D-“deficient” status, and after 6 months, 93% were of “sufficient” status (>75 nmol/L or 30 ng/L).42 By comparison, the Endocrine Society guidelines recommend 2,000 IU (50 |ag) per day or 50,000 IU (1,250 |j.g) weekly of vitamin D for at least 6 weeks or until serum concentrations of 25(OH)D are above 50 nmol/L (20 ng/mL).27 A new report investigating 25,000 IU weekly vitamin D supplementation of deficient/insufficient obese 8- to 18-year olds over 9 weeks found that it was well tolerated and resulted in advancement to “sufficient” status in more than 84% of participants.96 However, given the altered metabolism of vitamin D reported in the obese,64,97 it is questionable whether the dose required for maintenance in nonobese is the same as that required by the obese.
The obese are approximately half as efficient in using vitamin D compared to their lean counterparts.97,98 It has been estimated that 100 IU are required for every 2.5 nmol/L (1 ng/mL) increase in serum 25(OH)D concentration in the nonobese,99 whereas, in our study of obese adolescents, it took approximately 205 IU - more than double - of vitamin D for the same incremental increase.42 As further evidence of a higher dose required in obese children, a vitamin D supplementation study found that vitamin D deficiency persisted in 24% of obese versus 11% of nonobese African-American children given 400 IU per day for 4 weeks.100 Collectively, these findings argue for a separate set of guidelines for obese children and adolescents.
Vitamin D synthesis in the skin depends on the photoconversion of 7-dehydrocholestrol to previtamin D3 by ultraviolet B (UVB) light (wavelength =209-315 nm).101 Once formed, previtamin D3 undergoes heat-induced isomerization to vitamin D3.10 Vitamin D toxicity from skin synthesis is highly unlikely as prolonged exposure to sunlight photodegrades previtamin D3 to biologically inert isomers.102,103 Several factors affect the skin’s ability to produce vitamin D3. Season, latitude, and time of day affect vitamin D3 production by altering the absorption of UVB photons by the ozone layer.101,102 In the winter, the solar zenith angle of the sun is more diagonal at high latitudes causing the total number of photons reaching the Earth’s surface to diminish. During the day, UVB radiation is most intense when the sun is at its highest point, which occurs at midday. The application of sunscreen/block (sun protection factor as low as seven to eight blocks approximately 95% of previtamin D3 production),104 possessing greater amounts of melanin in one’s skin (acting as a natural sunscreen),105 and the use of clothing or other body covering also significantly decrease the production of vitamin D in the skin.102,103,106
UVB synthesis is one of the main sources of vitamin D in most populations tracked; however, due to the limited sun availability throughout the year in many locations and concerns for skin cancers, relying on this source for the treatment of vitamin D deficiency in childhood obesity is neither practical nor prudent. Likewise, obtaining adequate vitamin D from natural food sources alone is generally not achievable as only a limited number of foods naturally contain vitamin D. Among them, the most vitamin D rich are fish liver oils, fish, and organ meats, and to a lesser extent, egg yolks and sun-dried mushrooms.107
For those countries in which high levels of fish are not consumed, the only alternative to UVB light exposure is the use of fortified foods or dietary supplements. Commonly fortified foods include breakfast cereals, milk, milk products, grain products, pastas, margarine, and some brands of orange juice.11 In the USA, most vitamin D intake from foods is provided through fortification.108 In New Zealand, Australia, Canada, and the UK, fewer foods are fortified, and the prevalence of insufficiency is as low as or lower than observed in the USA.11,109,110
Even in countries that allow fortification, vitamin D intakes are low in those with dietary practices that limit the consumption of fortified foods.109 For example, the consumption of milk, the most common vehicle for vitamin D fortification, generally declines with increasing age in children.111 Therefore, in obese children, a population with apparently greater needs and prone to deficiency, vitamin D supplementation is warranted.
Both forms of the vitamin, D2 or D3, can be used as a food fortificant or dietary supplement, although D3 dominates.11 Some reports indicate that D2 is not as effective as D3, while others show no difference.112,113 In the USA, dietary supplements are readily available as over-the-counter (OTC) preparations and can contain up to 5,000 IU per capsule (which is not the case universally, eg, Australia).114 The D3 content of OTC is highly variable with potencies ranging from 9% to 146% of label claims.115 For medical use, prescription-grade supplements are available in the D2 form only.116 [Wrong – D3 from Bio-Tech since about 2012] Intramuscular (IM) vitamin D2 is also used to treat low-vitamin D status. The oral route is more efficacious than IM, but administration method should be based on patient’s choice, compliance, and availability as IM preparations are not available in all countries.117
Ingested vitamin D is presumed to follow the same fate as dietary lipids, although new data reveal that digestive and absorptive processes may be more complex than previously recognized as large interindividual variation in postprandial responses to vitamin D has been observed.118,119 During digestion, vitamin D is transferred to the mixed micelles generated by the lipolysis of dietary fat.120 Upon uptake through the brush border, vitamin D becomes incorporated into chylomicrons along with the other products of fat digestion, and approximately 80% is absorbed into the lymphatic system.121 D2 and D3 forms are similarly absorbed by the enterocyte.122-124 Total fat content of a meal does not appear to significantly alter vitamin D absorption;125 however, several fat-soluble molecules including dietary cholesterol, phytosterols, and vitamins A, E, and K have been shown to inhibit or compete with vitamin D for absorption.119,126,127 Further, any health conditions characterized by fat malabsorption can increase the risk for vitamin D deficiency.128
Vitamin D can accumulate throughout the body with adipose tissue as its primary storage site. It has a half-life of 4-6 weeks,129 although higher doses can lead to a long residence time.130,131 One laboratory performed a series of experiments to determine the relation between serum vitamin D3 and vitamin D status, as measured by serum concentration of 25(OH)D, in healthy adults after the oral administration of vitamin D3 across a broad range of intakes. Doses of 0-11,000 IU per day showed the increases in serum 25(OH)D to be biphasic: rapid conversion of vitamin D3 to 25(OH)D at physiological doses and slower rate of conversion at higher doses.132
Although vitamin D toxicity, defined as a serum concentration of 25(OH)D $375 nmol/L (150 ng/mL), in children is rare, health care providers should monitor children receiving treatment doses exceeding the upper ranges currently recommended.133 The IOM set a daily tolerable upper intake level of 2,500 IU (63 ug) for 1- to 3-year olds, 3,000 IU (75 ug) for 4- to 8-year olds, and 4,000 IU (100 ug) for 14- to 18-year olds,26 while the SAHM and Endocrine Society have endorsed an upper limit of 4,000 IU for all childhood age groups.27,29 There is insufficient evidence to guide the frequency of testing; however, it has been suggested that measurements of serum 25(OH)D be taken no more than every 6 months.133 In children with serum 25(OH)D concentrations above 375 nmol/L (150 ng/mL), serum calcium concentrations should also be monitored.133
Vitamin D deficiency is prevalent in childhood obesity. Excess adiposity is linked with poor vitamin D status, and the effects of this deficiency during obesity appear to have several health implications, including IR, inflammation, and compromised bone growth/mineralization. The rather ubiquitous distribution of VDR and the 1a-OH-ase throughout the body, including evidence of a role of vitamin D in adipogenesis and adipocyte metabolism, may in part explain these widespread consequences. Whether poor vitamin D status is a cause or an effect of obesity is not known; however, most of the findings to date suggest that the vitamin D needs of obese children are greater than the nonobese, and that weight loss can improve vitamin D status. Further research is required to define optimal vitamin D status and corresponding intake recommendations in this deficiency-prone population. Other investigations should focus on determining the clinical efficacy of vitamin D supplementation on the attenuation of the metabolic symptoms and conditions associated with childhood obesity. Finally, work is needed on the elucidation of the mechanisms by which vitamin D exerts its effects on obesity/adipose tissue and health.
- Ng M, Fleming T, Robinson M, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384(9945):766-781.
- Wang Y, Lim H. The global childhood obesity epidemic and the association between socio-economic status and childhood obesity. Int Rev Psychiatry. 2012;24:176-188.
- Committee on Accelerating Progress in Obesity Prevention, Food and Nutrition Board, Institute of Medicine. Accelerating Progress in Obesity Prevention: Solving the Weight of the Nation. Washington, DC: National Academies Press; 2012.
- Abrams P, Levitt Katz LE. Metabolic effects of obesity causing disease in childhood. Curr Opin Endocrinol Diabetes Obes. 2011;18:23-27.
- Campbell F, Conti G, Heckman JJ, et al. Early childhood investments substantially boost adult health. Science. 2014;343:1478-1485.
- Olshansky SJ, Passaro DJ, Hershow RC, et al. A potential decline in life expectancy in the United States in the 21st century. N Engl J Med. 2005;352:1138-1145.
- Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008;87:1080S-1086S.
- Foss YJ. Vitamin D deficiency is the cause of common obesity. Med Hypotheses. 2009;72:314-321.
- DeLuca HF. History of the discovery of vitamin D and its active metabolites. Bonekey Rep. 2014;3:479.
- Holick MF. Vitamin D. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. Modern Nutrition in Health and Disease. 10th ed. Baltimore, MD: Lippincott Williams and Wilkins; 2006:376-395.
- Macdonald HM. Contributions of sunlight and diet to vitamin D status. Calcif Tissue Int. 2013;92:163-176.
- Li J, Byrne ME, Chang E, et al. 1alpha,25-Dihydroxyvitamin D hydroxylase in adipocytes. J Steroid Biochem Mol Biol. 2008;112:122-126.
- Zehnder D, Bland R, Williams MC, et al. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab. 2001;86:888-894.
- Jones G. Extrarenal vitamin D activation and interactions between vitamin D(2), vitamin D(3), and vitamin D analogs. Annu Rev Nutr. 2013;33:23-44.
- Schwartz JB, Lai J, Lizaola B, et al. A comparison of measured and calculated free 25(OH) vitamin D levels in clinical populations. J Clin Endocrinol Metab. 2014;99:1631-1637.
- Wang Y, Zhu J, DeLuca HF. Where is the vitamin D receptor? Arch Biochem Biophys. 2012;523:123-133.
- Haussler MR, Whitfield GK, Kaneko I, et al. Molecular mechanisms of vitamin D action. Calcif Tissue Int. 2013;92:77-98.
- Kremer R, Campbell PP, Reinhardt T, Gilsanz V Vitamin D status and its relationship to body fat, final height, and peak bone mass in young women. J Clin Endocrinol Metab. 2009;94:67-73.
- Ding C, Gao D, Wilding J, Trayhurn P, Bing C. Vitamin D signalling in adipose tissue. Br J Nutr. 2012;108:1915-1923.
- Mitri J, Dawson-Hughes B, Hu FB, Pittas AG. Effects of vitamin D and calcium supplementation on pancreatic beta cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the calcium and vitamin D for diabetes mellitus (CaDDM) randomized controlled trial. Am J Clin Nutr. 2011;94:486-494.
- O’Riordan JL, Bijvoet OL. Rickets before the discovery of vitamin D. Bonekey Rep. 2014;3:478.
- Prentice A. Vitamin D deficiency: a global perspective. Nutr Rev. 2008;66:S153-S164.
- Raiten DJ, Picciano MF. Vitamin D and health in the 21st century: bone and beyond. Executive summary. Am J Clin Nutr. 2004;80: 1673S-1677S.
- Holick MF. Vitamin D: extraskeletal health. Endocrinol Metab Clin North Am. 2010;39:381-400.
- Brannon PM, Yetley EA, Bailey RL, Picciano MF. Overview of the conference “vitamin D and health in the 21st century: an update”. Am J Clin Nutr. 2008;88:483S-490S.
- Ross AC. The 2011 report on dietary reference intakes for calcium and vitamin D. Public Health Nutr. 2011;14:938-939.
- Holick MF, Binkley NC, Bischoff-Ferrari HA, et al; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911-1930.
- Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008;122:398-417.
- Harel Z, Cromer B, DiVasta AD, Gordon CM. Recommended vitamin D intake and management of low vitamin D status in adolescents: a position statement of the society for adolescent health and medicine. J Adolesc Health. 2013;52:801-803.
- Hossein-nezhad A, Holick MF. Vitamin D for health: a global perspective. Mayo Clin Proc. 2013;88:720-755.
- Wahl DA, Cooper C, Ebeling PR, et al. A global representation of vitamin D status in healthy populations. Arch Osteoporos. 2012;7: 155-172.
- Shin YH, Shin HJ, Lee YJ. Vitamin D status and childhood health. Korean JPediatr. 2013;56:417-423.
- Turer CB, Lin H, Flores G. Prevalence of vitamin D deficiency among overweight and obese US children. Pediatrics. 2013;131:e152-e161.
- Bellone S, Esposito S, Giglione E, et al. Vitamin D levels in a paediatric population of normal weight and obese subjects. J Endocrinol Invest. 2014;37(9):805-809.
- Gonzalez-Molero I, Rojo-Martinez G, Morcillo S, et al. Hypovitaminosis D and incidence of obesity: a prospective study. Eur J Clin Nutr. 2013;67:680-682.
- Lourenco BH, Qi L, Willett WC, Cardoso MA. FTO genotype, vitamin D status, and weight gain during childhood. Diabetes. 2014;63: 808-814.
- Vimaleswaran KS, Berry DJ, Lu C, et al; Genetic Investigation of Anthropometric Traits-GIANT Consortium. Causal relationship between obesity and vitamin D status: bi-directional mendelian randomization analysis of multiple cohorts. PLoS Med. 2013;10: e1001383.
- Morrison JA, Friedman LA, Gray-McGuire C. Metabolic syndrome in childhood predicts adult cardiovascular disease 25 years later: the Princeton Lipid Research Clinics Follow-up Study. Pediatrics. 2007;120: 340-345.
- Morrison JA, Friedman LA, Wang P, Glueck CJ. Metabolic syndrome in childhood predicts adult metabolic syndrome and type 2 diabetes mellitus 25 to 30 years later. J Pediatr. 2008;152:201-206.
- Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab. 2007;92:2017-2029.
- Peterson CA, Tosh AK, Belenchia AM. Vitamin D insufficiency and insulin resistance in obese adolescents. Ther Adv Clin Endocrinol Metab. 2014;5(6):166-189.
- Belenchia AM, Tosh AK, Hillman LS, Peterson CA. Correcting vitamin D insufficiency improves insulin sensitivity in obese adolescents: a randomized controlled trial. Am J Clin Nutr. 2013;97:774-781.
- George PS, Pearson ER, Witham MD. Effect of vitamin D supplementation on glycaemic control and insulin resistance: a systematic review and meta-analysis. Diabet Med. 2012;29:e142-e150.
- Kramer CK, Swaminathan B, Hanley AJ, et al. Prospective associations of vitamin D status with beta-cell function, insulin sensitivity and glycemia: the impact of parathyroid hormone status. Diabetes. 2014; 63(11):3868-3879.
- Alemzadeh R, Kichler J, Babar G, Calhoun M. Hypovitaminosis D in obese children and adolescents: relationship with adiposity, insulin sensitivity, ethnicity, and season. Metabolism. 2008;57:183-191.
- Dolinsky DH, Armstrong S, Mangarelli C, Kemper AR. The association between vitamin D and cardiometabolic risk factors in children: a systematic review. Clin Pediatr (Phila). 2013;52:210-223.
- Marzuillo P, Del Giudice EM, Santoro N. Pediatric non-alcoholic fatty liver disease: new insights and future directions. World J Hepatol. 2014;6:217-225.
- Pirgon O, Cekmez F, Bilgin H, Eren E, Dundar B. Low 25-hydroxyvitamin D level is associated with insulin sensitivity in obese adolescents with non-alcoholic fatty liver disease. Obes Res Clin Pract. 2013;7: e275-e283.
- Yildiz I, Erol OB, Toprak S, et al. Role of vitamin D in children with hepatosteatosis. J Pediatr Gastroenterol Nutr. 2014;59:106-111.
- Black LJ, Jacoby P, She Ping-Delfos WC, et al. Low serum 25- hydroxyvitamin D concentrations associate with non-alcoholic fatty liver disease in adolescents independent of adiposity. J Gastroenterol Hepatol. 2014;29:1215-1222.
- Katz K, Brar PC, Parekh N, Liu YH, Weitzman M. Suspected nonalcoholic fatty liver disease is not associated with vitamin d status in adolescents after adjustment for obesity. J Obes. 2010;2010:496829.
- National Institutes of Health. Osteoporosis prevention, diagnosis, and therapy. NIH Consens Statement. 2000;17:1-45.
- Whiting SJ. Obesity is not protective for bones in childhood and adolescence. Nutr Rev. 2002;60:27-30.
- Leonard MB, Shults J, Wilson BA, Tershakovec AM, Zemel BS. Obesity during childhood and adolescence augments bone mass and bone dimensions. Am J Clin Nutr. 2004;80:514-523.
- Junior IF, Cardoso JR, Christofaro DG, Codogno JS, de Moraes AC, Fernandes RA. The relationship between visceral fat thickness and bone mineral density in sedentary obese children and adolescents. BMC Pediatr. 2013;13:37.
- Pirgon O, Bilgin H, Tolu I, Odabas D. Correlation of insulin sensitivity with bone mineral status in obese adolescents with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf). 2011;75:189-195.
- Nobrega da Silva V, Goldberg TB, Mosca LN, Bisi Rizzo AC, Teixeira AS, Corrente JE. Metabolic syndrome reduces bone mineral density in overweight adolescents. Bone. 2014;66:1-7.
- Pacifico L, Bezzi M, Lombardo CV et al. Adipokines and C-reactive protein in relation to bone mineralization in pediatric nonalcoholic fatty liver disease. World JGastroenterol. 2013;19:4007-4014.
- Klein KO, Larmore KA, de LE, Brown JM, Considine RV Hassink SG. Effect of obesity on estradiol level, and its relationship to leptin, bone maturation, and bone mineral density in children. J Clin Endocrinol Metab. 1998;83:3469-3475.
- Dimitri P, Wales JK, Bishop N. Adipokines, bone-derived factors and bone turnover in obese children; evidence for altered fat-bone signalling resulting in reduced bone mass. Bone. 2011;48:189-196.
- Boucher-Berry C, Speiser PW, Carey DE, et al. Vitamin D, osteocalcin, and risk for adiposity as comorbidities in middle school children. J Bone Miner Res. 2012;27:283-293.
- Heaney RP. The Vitamin D requirement in health and disease. J Steroid Biochem Mol Biol. 2005;97:13-19.
- Maguire JL, Birken C, Thorpe KE, Sochett EB, Parkin PC. Parathyroid hormone as a functional indicator of vitamin D sufficiency in children. JAMA Pediatr. 2014;168:383-385.
- Drincic AT, Armas LA, Van Diest EE, Heaney RP. Volumetric dilution, rather than sequestration best explains the low vitamin D status of obesity. Obesity (Silver Spring). 2012;20:1444-1448.
- Wolden-Kirk H, Overbergh L, Gysemans C, et al. Unraveling the effects of 1,25OH2D3 on global gene expression in pancreatic islets. J Steroid Biochem Mol Biol. 2013;136:68-79.
- Mei Z, Grummer-Strawn LM, Pietrobelli A, Goulding A, Goran MI, Dietz WH. Validity of body mass index compared with other body- composition screening indexes for the assessment of body fatness in children and adolescents. Am J Clin Nutr. 2002;75:978-985.
- Mutt SJ, Hypponen E, Saarnio J, Jarvelin MR, Herzig KH. Vitamin D and adipose tissue-more than storage. Front Physiol. 2014;5:228.
- Lehr S, Hartwig S, Sell H. Adipokines: a treasure trove for the discovery of biomarkers for metabolic disorders. Proteomics Clin Appl. 2012;6:91-101.
- Lehr S, Hartwig S, Lamers D, et al. Identification and validation of novel adipokines released from primary human adipocytes. Mol Cell Proteomics. 2012;11:M111.
- Zoico E, Franceschetti G, Chirumbolo S, et al. Phenotypic shift of adipocytes by cholecalciferol and 1alpha,25 dihydroxycholecalciferol in relation to inflammatory status and calcium content. Endocrinology. 2014;155:4178 188.
- Peterson CA, Heffernan ME. Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25(OH)D concentrations in healthy women. JInflamm (Lond). 2008;5:10.
- Laird E, McNulty H, Ward M, et al. Vitamin D deficiency is associated with inflammation in older Irish adults. J Clin Endocrinol Metab. 2014;99:1807-1815.
- Vilarrasa N, Vendrell J, Maravall J, et al. Is plasma 25(OH) D related to adipokines, inflammatory cytokines and insulin resistance in both a healthy and morbidly obese population? Endocrine. 2010;38: 235-242.
- Ding C, Wilding JP, Bing C. 1,25-dihydroxyvitamin D3 protects against macrophage-induced activation of NFkappaB and MAPK signalling and chemokine release in human adipocytes. PLoS One. 2013;8:e61707.
- Creo AL, Rosen JS, Ariza AJ, Hidaka KM, Binns HJ. Vitamin D levels, insulin resistance, and cardiovascular risks in very young obese children. J Pediatr Endocrinol Metab. 2013;26:97-104.
- Smotkin-Tangorra M, Purushothaman R, Gupta A, Nejati G, Anhalt H, Ten S. Prevalence of vitamin D insufficiency in obese children and adolescents. J Pediatr Endocrinol Metab. 2007;20:817-823.
- Bailey RL, Dodd KW, Goldman JA, et al. Estimation of total usual calcium and vitamin D intakes in the United States. JNutr. 2010;140: 817-822.
- Al-Othman A, Al-Musharaf S, Al-Daghri NM, et al. Effect of physical activity and sun exposure on vitamin D status of Saudi children and adolescents. BMC Pediatr. 2012;12:92.
- Lagunova Z, Porojnicu AC, Lindberg FA, Aksnes L, Moan J. Vitamin D status in Norwegian children and adolescents with excess body weight. Pediatr Diabetes. 2011;12:120-126.
- Burt Solorzano CM, McCartney CR. Obesity and the pubertal transition in girls and boys. Reproduction. 2010;140:399 10.
- Travers SH, Jeffers BW, Bloch CA, Hill JO, Eckel RH. Gender and tanner stage differences in body composition and insulin sensitivity in early pubertal children. J Clin Endocrinol Metab. 1995;80:172-178.
- Hannon TS, Janosky J, Arslanian SA. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Pediatr Res. 2006;60:759-763.
- Buyukinan M, Ozen S, Kokkun S, Saz EU. The relation of vitamin D deficiency with puberty and insulin resistance in obese children and adolescents. J Pediatr Endocrinol Metab. 2012;25:83-87.
- Khadgawat R, Thomas T, Gahlot M, et al. The effect of puberty on interaction between vitamin D status and insulin resistance in obese Asian-Indian children. Int J Endocrinol. 2012;2012:173581.
- Kelly A, Brooks LJ, Dougherty S, Carlow DC, Zemel BS. A crosssectional study of vitamin D and insulin resistance in children. Arch Dis Child. 2011;96:447-452.
- Ortega RM, Aparicio A, Rodriguez-Rodriguez E, et al. Preliminary data about the influence of vitamin D status on the loss of body fat in young overweight/obese women following two types of hypocaloric diet. Br J Nutr. 2008;100:269-272.
- Pathak K, Soares MJ, Calton EK, Zhao Y, Hallett J. Vitamin D supplementation and body weight status: a systematic review and meta-analysis of randomized controlled trials. Obes Rev. 2014;15:528-537.
- St-Onge MP, Goree LL, Gower B. High-milk supplementation with healthy diet counseling does not affect weight loss but ameliorates insulin action compared with low-milk supplementation in overweight children. J Nutr. 2009;139:933-938.
- El-Hajj Fuleihan G, Nabulsi M, Tamim H, et al. Effect of vitamin D replacement on musculoskeletal parameters in school children: a randomized controlled trial. J Clin Endocrinol Metab. 2006;91: 405-412.
- Reinehr T, de Sousa G, Alexy U, Kersting M, Andler W. Vitamin D status and parathyroid hormone in obese children before and after weight loss. Eur J Endocrinol. 2007;157:225-232.
- Rock CL, Emond JA, Flatt SW, et al. Weight loss is associated with increased serum 25-hydroxyvitamin D in overweight or obese women. Obesity (Silver Spring). 2012;20:2296-2301.
- Tzotzas T, Papadopoulou FG, Tziomalos K, et al. Rising serum 25-hydroxy-vitamin D levels after weight loss in obese women correlate with improvement in insulin resistance. J Clin Endocrinol Metab. 2010;95:4251^257.
- Braegger C, Campoy C, Colomb V, et al; ESPGHAN Committee on Nutrition. Vitamin D in the healthy European paediatric population. J Pediatr Gastroenterol Nutr. 2013;56:692-701.
- Wagner CL, Greer FR. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008;122:1142-1152.
- Pramyothin P, Holick MF. Vitamin D supplementation: guidelines and evidence for subclinical deficiency. Curr Opin Gastroenterol. 2012;28:139-150.
- Radhakishun NN, van Vliet M, Poland DC, et al. Efficacy and tolerability of a high loading dose (25,000 IU weekly) vitamin D3 supplementation in obese children with vitamin D insufficiency/deficiency. Horm Res Paediatr. 2014;82:103-106.
- Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. 2000;72: 690-693.
- Dhaliwal R, Mikhail M, Feuerman M, Aloia JF. The vitamin D dose response in obesity. Endocr Pract. 2014;20:1258-1264.
- Holick MF, Biancuzzo RM, Chen TC, et al. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. JClin EndocrinolMetab. 2008;93:677-681.
- Rajakumar K, Fernstrom JD, Holick MF, Janosky JE, Greenspan SL. Vitamin D status and response to Vitamin D(3) in obese vs non- obese African American children. Obesity (Silver Spring). 2008; 16: 90-95.
- Holick MF, Jenkins M. The UVAdvantage. New York: ibooks; 2003.
- Webb AR, Engelsen O. Calculated ultraviolet exposure levels for a healthy vitamin D status. Photochem Photobiol. 2006;82: 1697-1703.
- Wacker M, Holick MF. Sunlight and Vitamin D: a global perspective for health. Dermatoendocrinol. 2013;5:51-108.
- Holick MF, Matsuoka LY, Wortsman J. Regular use of sunscreen on vitamin D levels. Arch Dermatol. 1995;131:1337-1339.
- Matsuoka LY, Wortsman J, Haddad JG, Kolm P, Hollis BW. Racial pigmentation and the cutaneous synthesis of vitamin D. Arch Dermatol. 1991;127:536-538.
- Hall LM, Kimlin MG, Aronov PA, et al. Vitamin D intake needed to maintain target serum 25-hydroxyvitamin D concentrations in participants with low sun exposure and dark skin pigmentation is substantially higher than current recommendations. JNutr. 2010;140:542-550.
- Schmid A, Walther B. Natural vitamin D content in animal products. Adv Nutr. 2013;4:453-462.
- Holden JM, Lemar LE, Exler J. Vitamin D in foods: development of the US Department of Agriculture database. Am J Clin Nutr. 2008;87: 1092S-1096S.
- Calvo MS, Whiting SJ, Barton CN. Vitamin D intake: a global perspective of current status. J Nutr. 2005;135:310-316.
- Whiting SJ, Green TJ, Calvo MS. Vitamin D intakes in North America and Asia-Pacific countries are not sufficient to prevent vitamin D insufficiency. J Steroid Biochem Mol Biol. 2007;103:626-630.
- Dror DK, Allen LH. Dairy product intake in children and adolescents in developed countries: trends, nutritional contribution, and a review of association with health outcomes. Nutr Rev. 2014;72:68-81.
- Biancuzzo RM, Clarke N, Reitz RE, Travison TG, Holick MF. Serum concentrations of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in response to vitamin D2 and vitamin D3 supplementation. J Clin Endocrinol Metab. 2013;98:973-979.
- Tripkovic L, Lambert H, Hart K, et al. Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr. 2012;95: 1357-1364.
- Bilinski K, Talbot P Vitamin d supplementation in australia: implications for the development of supplementation guidelines. J Nutr Metab. 2014;2014:374208.
- LeBlanc ES, Perrin N, Johnson JD Jr, Ballatore A, Hillier T. Over- the-counter and compounded vitamin D: is potency what we expect? JAMA Intern Med. 2013;173:585-586.
- Demetriou ET, Travison TG, Holick MF. Treatment with 50,000 IU vitamin D(2) every other week and effect on serum 25-hydroxyvitamin D(2), 25-hydroxyvitamin D(3), and total 25-hydroxyvitamin D in a clinical setting. Endocr Pract. 2012;18:399-402.
- Zabihiyeganeh M, Jahed A, Nojomi M. Treatment of hypovitaminosis D with pharmacologic doses of cholecalciferol, oral vs intramuscular; an open labeled RCT. Clin Endocrinol (Oxf). 2013;78:210-216.
- Masson CJ, Plat J, Mensink RP, et al. Fatty acid- and cholesterol transporter protein expression along the human intestinal tract. PLoS One. 2010;5:e10380.
- Reboul E, Goncalves A, Comera C, et al. Vitamin D intestinal absorption is not a simple passive diffusion: evidences for involvement of cholesterol transporters. Mol Nutr Food Res. 2011;55:691-702.
- Rautureau M, Rambaud JC. Aqueous solubilisation of vitamin D3 in normal man. Gut. 1981;22:393-397.
- Reboul E. Intestinal absorption of vitamin D: from the meal to the enterocyte. Food Funct. 2015.
- Armas LA, Hollis BW, Heaney RP. Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab. 2004;89: 5387-5391.
- Biancuzzo RM, Young A, Bibuld D, et al. Fortification of orange juice with vitamin D(2) or vitamin D(3) is as effective as an oral supplement in maintaining vitamin D status in adults. Am J Clin Nutr. 2010;91: 1621-1626.
- Romagnoli E, Mascia ML, Cipriani C, et al. Short and long-term variations in serum calciotropic hormones after a single very large dose of ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) in the elderly. J Clin Endocrinol Metab. 2008;93:3015-3020.
- Wagner D, Sidhom G, Whiting SJ, Rousseau D, Vieth R. The bioavailability of vitamin D from fortified cheeses and supplements is equivalent in adults. J Nutr. 2008;138:1365-1371.
- Borel P, Caillaud D, Cano NJ. Vitamin D bioavailability: state of the art. Crit Rev Food Sci Nutr. 2013.
- Goncalves A, Gleize B, Bott R, et al. Phytosterols can impair vitamin D intestinal absorption in vitro and in mice. Mol Nutr Food Res. 2011; 55(Suppl 2):S303-S311.
- Holick MF, Vitamin D deficiency, NEngl J Med. 2007;357:266-281.
- Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003;77:204-210.
- Rosenstreich SJ, Rich C, Volwiler W. Deposition in and release of vitamin D3 from body fat: evidence for a storage site in the rat. J Clin Invest. 1971;50:679-687.
- Wu F, Staykova T, Horne A, et al. Efficacy of an oral, 10-day course of high-dose calciferol in correcting vitamin D deficiency. N Z Med J. 2003;116:U536.
- Heaney RP, Armas LA, Shary JR, Bell NH, Binkley N, Hollis BW. 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions. Am J Clin Nutr. 2008;87: 1738-1742.
- Vogiatzi MG, Jacobson-Dickman E, DeBoer MD. Vitamin D supplementation and risk of toxicity in pediatrics: a review of current literature. J Clin Endocrinol Metab. 2014;99:1132-1141.