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

#### **2.1. Vitamin D**

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 exposure to the sun [20].

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 formed from the precursor 7-dehydrocholesterol to give pre-VD3 and further is released into the circulation [21]. Vitamin D3, whether derived from sunlight or the diet, enters the circulation bound to vitamin D–binding protein (DBP) and is transported to the liver. VD3 is hydroxylated in the liver to 25(OH)D, the major circulating vitamin D metabolite; it has a relatively long half-life (15 days) but, however, is an inactive form. The Institute of Medicine proposed that serum 25(OH)D concentrations below 50 nmol/l or 20 ng/ml should be considered to represent the deficiency of this nutrient [22]. 25(OH)D is then further hydroxylated by 1α-hydroxylase enzyme (gene: CYP27B1), and this occurs primarily in the kidney to produce 1,25(OH)2D, the biologically active form of VD [23, 24].

In relation of signaling of VD in AT, 25(OH)D can promote the differentiation of human adipocytes, most likely via its activation to 1,25(OH)2D [25]. The local metabolism of VD in AT may regulate the conversion of preadipocytes to adipocytes and later support the healthy remodeling of human AT. Also, 1,25(OH)2D may promote the differentiation of human preadipocytes by maintaining a high expression level of key adipogenic transcription factors, like C/EBPα and PPAR*γ* gene expression, the two master regulators of adipogenesis that were increased during the late phase of differentiation [26]. Besides, 1,25-dihydroxyvitamin D modulates adipogenesis through VDR-dependent inhibition of critical molecular components of it such as PPAR*γ* [27].

The emerging role of VD in immune regulation suggests that this endocrine factor can modulate the inflammatory responses in AT. 1,25(OH)2D displayed an anti-inflammatory effect and its ability to improve the insulin-stimulated uptake of glucose, as well as enhance and improve the function of pancreatic β-cell [28]. To strongly support the anti-inflammatory effect of 1,25(OH)2D in adipocytes, the improvement of pro-inflammatory status and glucose uptake in adipocytes under 1,25(OH)2D effect suggest that low-grade inflammation could be linked to VDD [29].

The 1,25(OH)2D significantly reduced the basal release of MCP-1, IL-8, and IL-6 from preadipocytes (MCP-1 is produced by macrophages which increase further macrophage infiltration into AT [30], and circulating levels of IL-8 are increased in obesity). It should also be pointed out that since adipocytes store VD, adipocytes and monocytes/macrophages are able to locally convert 25(OH)D to 1,25(OH)2D [31, 32], and the concentrations of VD within AT could be higher than implied by the plasma levels. Vitamin D3 may protect against AT inflammation in obesity by disrupting the deleterious cycle of macrophage recruitment [33].

Lower 25(OH)D is associated with greater regional adiposity; this is stronger in VAT than SAT and significant across the spectrum of body size [34]. VD has been reported to act as an acute phase reactant as a consequence of such an inflammatory response occurs in obesity, which can suppress the concentration of 25(OH)D [35].
