**2.2. Vitamin D receptor**

other cells are also present including preadipocytes, mast cells, and macrophages, which also contribute to this inflammatory environment. Currently and worldwide, obesity is the fifth greatest risk factor for mortality [6], and it is associated with vitamin D deficiency (VDD) [7]. Vitamin D (VD) is essential for the development and maintenance of bone tissue, as well as for normal homeostasis of calcium and phosphorus [8]. Moreover, VD has other major functional roles; it is related to differentiation, cell proliferation, and hormone secretion. It is an important nutrient with crucial role in obesity onset (AT) and in the comorbidities associated with the

An estimated 80–90% of VD from the human body originates from skin synthesis, with sunlight activation, while the rest is supplied through supplements or food [10]. VD status is measured by means of the plasma levels of 25-hydroxyvitamin D [25(OH)D] or calcidiol, the dominant circulating form and the best indicator of VD status [11]. The action of 1,25(OH)2D, active form of VD [12], is mediated through the vitamin D receptor (VDR), a member of the nuclear receptor

The VDR signaling pathway is crucial for the proper functioning of AT that is called an active endocrine organ, which plays an important role in fat storage and in the production and secretion of adipokines [14, 15]; is a reservoir for VD; and, besides, can activate/inactivate it by hydroxylation. VD and VDR are implicated in preadipocyte differentiation into adipocytes

Major differences between subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were shown in the expression of VD-metabolizing enzymes. The expression of the VDR, 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1) genes, and 24-hydroxylase enzymes has

In line, our chapter will focus on VD status and expression of VDR and VD hydroxylase

VD is a hormone mainly described for its role as a regulator of phosphate and calcium homeostasis [18, 19], therefore playing an important part in bone metabolism, and seems to have some anti-inflammatory and immune-modulating properties. This micronutrient can be obtained through animal (VD3, cholecalciferol) or plant (VD2, ergocalciferol) food sources. However, vitamin D3 is the only form that is found naturally in human subjects and other animals. Although the main source of vitamin D3 is through endogenous synthesis in the skin, the vitamin can also be obtained from the diet, and this is important for those who have limited

VD3 is produced endogenously in the skin after UVB irradiation, between 290 and 315 nm, present for limited number of hours also varying with respect to latitude and reason. VD3 is

**2. Vitamin D, VDR, and hydroxylase enzymes on adipose tissue**

superfamily, which regulates the transcription of many target genes [13].

chronic inflammation [9].

144 Adiposity - Omics and Molecular Understanding

been shown in human adipocytes [17].

enzymes in SAT and VAT in an obese environment.

[16].

**2.1. Vitamin D**

exposure to the sun [20].

The human VDR is a 50- to 60-kDa molecule, a member of the nuclear receptor superfamily that is the only nuclear receptor that binds to 1,25(OH)2D with high affinity and specificity. VDR forms a heterodimer with the retinoid X receptor acting as a transcription factor that binds to VD response elements in the promoter region of target genes [36]. VDR expression has been identified in most human tissues, including in osteoblasts, skin keratinocytes, macrophages, smooth muscle, pancreatic β-cells and epithelial cells [37, 38], and it is also highly expressed in adipocytes.

The action of 1,25(OH)2D is mediated through the VDR, which regulates the transcription of many target genes [13]. There are more than 1000 genes that are directly or indirectly regulated by 1,25(OH)2D and involved in various physiological processes such as cell proliferation, differentiation, apoptosis, and angiogenesis [38].

VDR expression is increased in obese, which has more VAT than lean subjects, but the physiological relevance of this upregulation has not yet been elucidated. VAT *VDR* gene expression correlated positively with body mass index (BMI) [39]. The ubiquitous expression of VDR may underlie the diverse effects of VD and provide a mechanistic basis for the link between VDD and a number of disorders that are linked with obesity like certain types of cancer, inflammatory bowel disease, cardiovascular diseases (CVD), diabetes (type 1 and type 2), and the metabolic syndrome [40–42].

Expanding to another approach, there are associations of VDR variants with the more metabolically active fat, VAT, which is more closely tied to the metabolic consequences of adiposity. Association of VDR SNP rs4,328,262 with VAT supports the notion that the VDR gene is likely to be related to the development of obesity and obesity-related outcomes [43]. Polymorphisms in the VDR gene might play a role in regulating AT activity body fatness and susceptibility to adiposity among African Americans, albeit genetic factors that contribute to adiposity are certainly more complex than to be explained totally by variations in a single gene.
