Genetic Factors and Molecular Mechanisms of Vitamin D and Obesity Relationship

Vitamin D (vitD) deficiency is associated with a wide range of chronic diseases and conditions, including obesity, and with an increasing severity of metabolic dysregulation, such as insulin resistance, hyperlipidemia, liver disease, and hypertension, both in children and adults. However, the nature of the association between low vitD status and obesity remains unclear. This fact has motivated the scientific community to conduct genetic association analyses between 25-hydroxyvitamin D (25[OH]D)-related genes and obesity traits. In this line, the variation in the vitD receptor (VDR) gene represents the bulk of the findings. Specifically, polymorphisms in the VDR gene have been associated with obesity traits in some but not all, studies. Thus, results regarding this matter remain inconclusive. Other genes aside from VDR have also been investigated in relation to obesity-related traits. However, again, findings have been inconsistent. In general, results point to the fact that the DBP/GC gene could be an important protein-linking obesity and vitD status. On the other hand, several studies have attempted to determine the molecular mechanism of the relationship between 25(OH)-D levels and obesity. Some of these studies suggest that vitD, due to its fat-soluble characteristic, is retained by the adipose tissue and has the capacity to metabolize 25(OH)-D locally, and this can be altered during obesity. Additionally, vitD is capable of regulating the gene expression related to adipogenesis process, inflammation, oxidative stress, and metabolism in mature adipocytes. Therefore, the aim of the present review was to evaluate the association between obesity and vitD deficiency describing the main molecular mechanism of the relationship and the link with genetic factors. Key Messages: Low serum 25(OH)-D is positively associated with obesity or BMI in adults and children. Circulating vitD concentrations are, at least, partially determined by genetic factors. VitD plays an important role in the adipogenesis process and inflammation status in adipocytes and adipose tissue.

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Association of the polymorphism of the vitamin D receptor gene (VDR) with the risk of leprosy in the Brazilian Amazon

Bioscience Reports ◽

10.1042/bsr20204102 ◽

2021 ◽

Author(s):

Jasna Letícia Pinto Paz ◽

Maria do Perpétuo Socorro Corrêa Amador Silvestre ◽

Letícia Siqueira Moura ◽

Ismari Perini Furlaneto ◽

Yan Corrêa Rodrigues ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Genetic Factors ◽

Receptor Gene ◽

Mycobacterium Leprae ◽

Nucleotide Polymorphisms ◽

Vdr Gene ◽

Single Nucleotide ◽

The Relationship

The transmission and evolution of leprosy depends on several aspects, including immunological and genetic factors of the host, as well as genetic factors of Mycobacterium leprae. This study evaluated the association of single nucleotide polymorphisms (SNPs) on the FokI (rs2228570), TaqI (rs731236), ApaI (rs7975232) regions of the vitamin D receptor (VDR) gene with leprosy. A total of 405 individuals were evaluated, composed by groups of 100 multibacillary and 57 paucibacillary patients, and 248 healthy contacts. Blood samples were collected from patients and contacts. The genotyping was performed by sequencing of the interest regions. The alleles of the studied SNPs, and of SNP FokI genotypes, were not associated with leprosy. For the SNP on TaqI region, the relationship between the tt genotype, and for the SNP ApaI, the AA genotype, revealed an association with susceptibility to MB form, while Aa genotype with protection. The extended genotypes AaTT and AaTt of ApaI and TaqI were associated with protection to against MB form. Futher studies analyzing the expression of the VDR gene and the correlation with its SNPs might help to clarify the role of polymorphisms on the immune response in leprosy.

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Vitamin D signalling in adipose tissue

British Journal Of Nutrition ◽

10.1017/s0007114512003285 ◽

2012 ◽

Vol 108 (11) ◽

pp. 1915-1923 ◽

Cited By ~ 161

Author(s):

Cherlyn Ding ◽

Dan Gao ◽

John Wilding ◽

Paul Trayhurn ◽

Chen Bing

Keyword(s):

Vitamin D ◽

Adipose Tissue ◽

Vitamin D Deficiency ◽

Vitamin D Metabolites ◽

Hydroxyvitamin D ◽

The Metabolic Syndrome ◽

Prevalence Of Obesity ◽

Adipose Tissue Development ◽

And Function

Vitamin D deficiency and the rapid increase in the prevalence of obesity are both considered important public health issues. The classical role of vitamin D is in Ca homoeostasis and bone metabolism. Growing evidence suggests that the vitamin D system has a range of physiological functions, with vitamin D deficiency contributing to the pathogenesis of several major diseases, including obesity and the metabolic syndrome. Clinical studies have shown that obese individuals tend to have a low vitamin D status, which may link to the dysregulation of white adipose tissue. Recent studies suggest that adipose tissue may be a direct target of vitamin D. The expression of both the vitamin D receptor and 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1) genes has been shown in murine and human adipocytes. There is evidence that vitamin D affects body fat mass by inhibiting adipogenic transcription factors and lipid accumulation during adipocyte differentiation. Some recent studies demonstrate that vitamin D metabolites also influence adipokine production and the inflammatory response in adipose tissue. Therefore, vitamin D deficiency may compromise the normal metabolic functioning of adipose tissue. Given the importance of the tissue in energy balance, lipid metabolism and inflammation in obesity, understanding the mechanisms of vitamin D action in adipocytes may have a significant impact on the maintenance of metabolic health. In the present review, we focus on the signalling role of vitamin D in adipocytes, particularly the potential mechanisms through which vitamin D may influence adipose tissue development and function.

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Vitamin D Status and Seasonal Variation among Danish Children and Adults: A Descriptive Study

Nutrients ◽

10.3390/nu10111801 ◽

2018 ◽

Vol 10 (11) ◽

pp. 1801 ◽

Cited By ~ 20

Author(s):

Louise Hansen ◽

Anne Tjønneland ◽

Brian Køster ◽

Christine Brot ◽

Rikke Andersen ◽

...

Keyword(s):

Vitamin D ◽

Seasonal Variation ◽

Vitamin D Status ◽

Hydroxyvitamin D ◽

Supplement Use ◽

Wide Range ◽

Adults And Children ◽

25 Hydroxyvitamin D ◽

Vitamin D Supplement ◽

Very High

The aim of the present study was to describe vitamin D status and seasonal variation in the general Danish population. In this study, 3092 persons aged 2 to 69 years (2565 adults, 527 children) had blood drawn twice (spring and autumn) between 2012 and 2014. A sub-sample of participants had blood samples taken monthly over a year. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were measured by liquid chromatography mass spectrometry, and information on supplement use was assessed from questionnaires. Seasonal variations in 25(OH)D concentrations were evaluated graphically and descriptively, and status according to age, sex, and supplement use was described. It was found that 86% of both adults and children were vitamin D-sufficient in either spring and or/autumn; however, many had a spring concentration below 50 nmol/L. A wide range of 25(OH)D concentrations were found in spring and autumn, with very low and very high values in both seasons. Among adults, women in general had higher median 25(OH)D concentrations than men. Furthermore, vitamin D supplement use was substantial and affected the median concentrations markedly, more so during spring than autumn. Seasonal variation was thus found to be substantial, and bi-seasonal measurements are vital in order to capture the sizable fluctuations in vitamin D status in this Nordic population.

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Vitamin D as a Principal Factor in Mediating Rheumatoid Arthritis-Derived Immune Response

BioMed Research International ◽

10.1155/2019/3494937 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 13

Author(s):

Muhammad M. Aslam ◽

Peter John ◽

Attya Bhatti ◽

Sidrah Jahangir ◽

M. I. Kamboh

Keyword(s):

Rheumatoid Arthritis ◽

Vitamin D ◽

Immune Responses ◽

Molecular Mechanisms ◽

Genetic Factors ◽

Autoimmune Disorder ◽

Serum Levels ◽

Principal Factor ◽

Phosphate Homeostasis ◽

Low Serum

Rheumatoid arthritis (RA) is a systemic multifactorial autoimmune disorder. The interactions between diverse environmental and genetic factors lead to the onset of this complex autoimmune disorder. Serum levels of vitamin D (VD) are involved in the regulation of various immune responses. Vitamin D is a key signaling molecule in the human body that maintains calcium as well as phosphate homeostasis. It also regulates the functions of the immune system and, thus, can play a substantial role in the etiology of various autoimmune disorders, including RA. Low serum VD levels have been found to be associated with a higher risk of RA, although this finding has not been replicated consistently. The molecular mechanisms by which VD influences autoimmunity need to be further explored to understand how variation in plasma VD levels could affect the pathogenesis of RA. This mini-review focuses on the influence of VD and its serum levels on RA susceptibility, RA-associated complexities, treatment, and transcriptome products of key proinflammatory cytokines, along with other cytokines that are key regulators of inflammation in rheumatoid joints.

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Relationship Between Level of Serum 25-Hydroxyvitamin D and Risk of Squamous Cell Carcinoma in an Iranian Population

Dermatology Practical & Conceptual ◽

10.5826/dpc.0904a06 ◽

2019 ◽

pp. 278-282

Author(s):

Mahboobeh-Sadat Hosseini ◽

Fereshteh Salarvand ◽

Amir Houshang Ehsani ◽

Pedram Noormohammadpour ◽

Shadi Azizzadeh ◽

...

Keyword(s):

Vitamin D ◽

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Outdoor Environment ◽

Hydroxyvitamin D ◽

Vitamin D Levels ◽

History Of ◽

25 Hydroxyvitamin D ◽

The Relationship

Background: The relationship between vitamin D and skin squamous cell carcinoma (SCC) is not well defined. Objective: To investigate the relationship between vitamin D levels and the incidence of skin SCC for the first time in Iran. Methods and Study Design: In this case-control study, 126 subjects were enrolled (63 in each group) out of referents to Razi Skin Hospital in Tehran in 2014. The risk factors for cancer gathered by self-reported questionnaires and blood samples were obtained to measure the level of 25-hydroxyvitamin D. Multivariate logistic regression was used to neutralize the effect of confounding factors. Results: Cases of SCC were more likely to be in men, older than 49 years and working in an outdoor environment, and with longtime exposure to sunlight and a personal history of skin cancers. Family history of skin cancer and of cigarette smoking were not significantly related to SCC. In the SCC and control groups, 69.8% and 31.7%, respectively, had sufficient levels of vitamin D (P < 0.001). Mean level of 25-hydroxyvitamin D was 40.99 ng/mL in the SCC group and 26.34 ng/mL in the control group (P < 0.05). In the unadjusted model, the level of vitamin D as a continuous variable was positively related to SCC risk. In the adjusted model, vitamin D did not independently predict the likelihood of SCC. Conclusion: Vitamin D level and SCC risk are directly related, although not in an independent fashion. Indeed, this relation is severely confounded by exposure to sunlight, which was evidenced by an increased vitamin D level in the people working outside and the higher prevalence of SCC in the same population.

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Chemotherapy Resistance Explained through Endoplasmic Reticulum Stress-Dependent Signaling

Cancers ◽

10.3390/cancers11030338 ◽

2019 ◽

Vol 11 (3) ◽

pp. 338 ◽

Cited By ~ 17

Author(s):

Entaz Bahar ◽

Ji-Ye Kim ◽

Hyonok Yoon

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Molecular Mechanism ◽

Molecular Mechanisms ◽

Cellular Proliferation ◽

Protein Quality ◽

Chemotherapy Resistance ◽

Persistent Problem ◽

Stress Dependent ◽

The Relationship

Cancers cells have the ability to develop chemotherapy resistance, which is a persistent problem during cancer treatment. Chemotherapy resistance develops through different molecular mechanisms, which lead to modification of the cancer cells signals needed for cellular proliferation or for stimulating an immune response. The endoplasmic reticulum (ER) is an important organelle involved in protein quality control, by promoting the correct folding of protein and ER-mediated degradation of unfolded or misfolded protein, namely, ER-associated degradation. Disturbances of the normal ER functions causes an accumulation of unfolded or misfolded proteins in the ER lumen, resulting in a condition called “ER stress (ERS).” ERS triggers the unfolded protein response (UPR)—also called the ERS response (ERSR)—to restore homeostasis or activate cell death. Although the ERSR is one emerging potential target for chemotherapeutics to treat cancer, it is also critical for chemotherapeutics resistance, as well. However, the detailed molecular mechanism of the relationship between the ERSR and tumor survival or drug resistance remains to be fully understood. In this review, we aim to describe the most vital molecular mechanism of the relationship between the ERSR and chemotherapy resistance. Moreover, the review also discusses the molecular mechanism of ER stress-mediated apoptosis on cancer treatments.

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Loss of Sirt6 in adipocytes impairs the ability of adipose tissue to adapt to intermittent fasting

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00664-1 ◽

2021 ◽

Vol 53 (9) ◽

pp. 1298-1306

Author(s):

Dandan Wu ◽

In Hyuk Bang ◽

Byung-Hyun Park ◽

Eun Ju Bae

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Molecular Mechanisms ◽

Intermittent Fasting ◽

Metabolic Profiles ◽

Wild Type ◽

High Fat ◽

Ad Libitum ◽

The Relationship ◽

Tissue Browning

AbstractIntermittent fasting (IF) is gaining popularity for its effectiveness in improving overall health, including its effectiveness in achieving weight loss and euglycemia. The molecular mechanisms of IF, however, are not well understood. This study investigated the relationship between adipocyte sirtuin 6 (Sirt6) and the metabolic benefits of IF. Adipocyte-specific Sirt6-knockout (aS6KO) mice and wild-type littermates were fed a high-fat diet (HFD) ad libitum for four weeks and then subjected to 12 weeks on a 2:1 IF regimen consisting of two days of feeding followed by one day of fasting. Compared with wild-type mice, aS6KO mice subjected to HFD + IF exhibited a diminished response, as reflected by their glucose and insulin intolerance, reduced energy expenditure and adipose tissue browning, and increased inflammation of white adipose tissue. Sirt6 deficiency in hepatocytes or in myeloid cells did not impair adaptation to IF. Finally, the results indicated that the impaired adipose tissue browning and reduced expression of UCP1 in aS6KO mice were accompanied by downregulation of p38 MAPK/ATF2 signaling. Our findings indicate that Sirt6 in adipocytes is critical to obtaining the improved glucose metabolism and metabolic profiles conferred by IF and that maintaining high levels of Sirt6 in adipocytes may mimic the health benefits of IF.

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Role of vitamin D and sFlt-1/PlGF ratio in the development of early- and late-onset preeclampsia

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2014-1039 ◽

2015 ◽

Vol 53 (7) ◽

Cited By ~ 8

Author(s):

Indira Álvarez-Fernández ◽

Belén Prieto ◽

Verónica Rodríguez ◽

Yolanda Ruano ◽

Ana I. Escudero ◽

...

Keyword(s):

Vitamin D ◽

Late Onset ◽

Tertiary Care ◽

Care Hospital ◽

Hydroxyvitamin D ◽

Increased Risk ◽

25 Hydroxyvitamin D ◽

The Relationship ◽

Plgf Ratio

AbstractThe imbalanced production of placental biomarkers and vitamin D deficiency have been proposed as risk factors for the development of preeclampsia (PE). However, little is known about the relationship between them and their role in early- versus late-onset PE. The objectives were to assess the role of 25-hydroxyvitamin D [25(OH)D] concentrations and the soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) ratio in the development of early- and late-onset PE; and to evaluate the relationship between 25(OH)D and the biomarkers.A retrospective, full-blinded cohort study was conducted at the Obstetric Emergency Service of a tertiary care hospital. Pregnant women (n=257) attending obstetric triage with suspicion of PE were included. sFlt-1, PlGF and 25(OH)D concentrations were measured by electrochemoluminescence (ECLIA) immunoassay and pregnancy outcome (development of PE) was registered from patients records.PE women showed lower 25(OH)D concentrations at clinical presentation than non-PE women (median: 35.0 nmol/L and 39.6 nmol/L, respectively; p=0.027). Women with 25(OH)D levels <50 nmol/L experienced an increased risk of developing late-onset PE [odds ratio (OR) 4.6, 95% confidence interval (CI) 1.4–15], but no association was found for early-onset PE. However, a sFlt-1/PlGF ratio above the corresponding cutpoints increased the risk of developing both early- and late-onset PE [ORs 58 (95% CI 11–312) and 12 (95% CI 5.0–27), respectively]. No association was found between 25(OH)D levels and sFlt-1/PlGF ratio.Low vitamin D status in women with suspected late-onset PE increases the risk of imminent development of the disease.

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Age-Related Changes in the 25-Hydroxyvitamin D Versus Parathyroid Hormone Relationship Suggest a Different Reason Why Older Adults Require More Vitamin D

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2002-021064 ◽

2003 ◽

Vol 88 (1) ◽

pp. 185-191 ◽

Cited By ~ 298

Author(s):

Reinhold Vieth ◽

Yasmin Ladak ◽

Paul G. Walfish

Keyword(s):

Older Adults ◽

Vitamin D ◽

Secondary Hyperparathyroidism ◽

Age Groups ◽

The Elderly ◽

Age Group ◽

Hydroxyvitamin D ◽

Age Related ◽

25 Hydroxyvitamin D ◽

The Relationship

Vitamin D requirements are thought to vary with age, but there is little comparative evidence for this. One goal in establishing a vitamin D requirement is to avoid secondary hyperparathyroidism. We studied 1741 euthyroid, thyroid clinic outpatients without evidence of calcium abnormalities, ranging in age from 19 to 97 yr, whose serum and urine had been analyzed for calcium, vitamin D, and parathyroid status. We found no effect of age on the 25-hydroxyvitamin D [25(OH)D] concentration associated with specific vitamin D intakes, and there was no relationship between 25(OH)D and 1,25hydroxyvitamin D [1,25(OH)2D]. In every age group, serum 1,25(OH)2D declined with increasing creatinine (P < 0.001). What changed with age included creatinine, which correlated with 25(OH)D (r = 0.146, P < 0.001) only in the youngest age group (19–50 yr) but not in the older age groups (P > 0.1). Creatinine did not correlate with PTH in the youngest age group, but the relationship became significant as age increased (e.g. for the elderly, r = 0.365, P < 0.001). Linear regression of log PTH vs. log 25(OH)D agreed with the natural shape of the relationship observed with scatterplot smoothing, and this showed no plateau in PTH as 25(OH)D increased. We compared PTH concentrations among age groups, based on 20 nmol/liter increments in 25(OH)D. Mean PTH in adults older than 70 yr was consistently higher than in adults younger than 50 yr (P < 0.05 by ANOVA and Dunnett’s t test). PTH levels of the elderly who had 25(OH)D concentrations greater than 100 nmol/liter matched PTH of younger adults having 25(OH)D concentrations near 70 nmol/liter. This study shows that all age groups exhibit a high prevalence of 25(OH)D insufficiency and secondary hyperparathyroidism. Older adults are just as efficient in maintaining 25(OH)D, but they need more vitamin D to produce the higher 25(OH)D concentrations required to overcome the hyperparathyroidism associated with their diminishing renal function.

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Very high rates of vitamin D insufficiency in women of child-bearing age living in Beijing and Hong Kong

British Journal Of Nutrition ◽

10.1017/s0007114507844382 ◽

2008 ◽

Vol 99 (6) ◽

pp. 1330-1334 ◽

Cited By ~ 43

Author(s):

Jean Woo ◽

Christopher W. K. Lam ◽

Jason Leung ◽

Winny Y. Lau ◽

Edith Lau ◽

...

Keyword(s):

Vitamin D ◽

Hong Kong ◽

Pregnant Women ◽

Vitamin D Deficiency ◽

Vitamin D Insufficiency ◽

Dietary Intakes ◽

Hydroxyvitamin D ◽

The North ◽

25 Hydroxyvitamin D ◽

The Relationship

We aimed to describe the vitamin D status of young women living in two Chinese cities in the spring – Beijing in the north (latitude 39° north) and Hong Kong (latitude 22° north) in the south. We also examined the relationship between serum 25-hydroxyvitamin D and parathyroid hormone (PTH) concentrations to determine a threshold for serum 25-hydroxyvitamin D above which there is no further suppression of PTH. Finally, we examined whether dietary Ca intake influences this relationship. Non-pregnant women aged 18–40 years (n 441) were recruited between February and June. Fasting blood was collected and dietary intakes were assessed using 5 d food records. Mean serum 25-hydroxyvitamin D concentration was lower in Beijing than Hong Kong women (29 v. 34 nmol/l; P < 0·001). Vitamin D deficiency ( ≤ 25 nmol/l) was indicated in 40 % of Beijing and 18 % of Hong Kong women, and over 90 % of women in both cities were insufficient ( ≤ 50 nmol/l). Mean Ca and vitamin D intakes were 478 mg/d and 2·0 μg/d, respectively. The relationship between 25-hydroxyvitamin D concentration and PTH was linear throughout the range with a slope of − 0·36 (different from 0; P < 0·001; R 0·26), with no apparent threshold. There was no influence of Ca intake on the relationship between 25-hydroxyvitamin D and PTH concentration. Vitamin D deficiency is common and insufficiency is very common in non-pregnant women in Hong Kong and Beijing during spring. Serum 25-hydroxyvitamin D was inversely associated with PTH with no apparent threshold. Strategies such as vitamin D fortification or supplementation may be required.

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