**3.2. Low 1.25(OH)2D inhibits adipogenesis**

Some experimental data have suggested that VDD can favor greater adiposity by promoting increased PTH hormone levels and greater inflow of calcium into adipocytes, so increasing lipogenesis [68]. Evidence suggests that low 1.25(OH)2D inhibits adipogenesis through actions modulated by vitamin D-dependent receptors [69]. Thus, depletion of vitamin D can lead to excessive differentiation of preadipocytes to adipocytes.

#### **3.3. Negative feedback control**

Excess AT impairs the VD status from activating energy expenditure. In this mechanism, the leptin stimulates osteocytic FGF23, inhibits renal synthesis of 1α-hydroxylase, and consequently impairs the production of 1,25 (OH)2D, creating a negative feedback mechanism [70].

#### **3.4. Sequestration in adipose tissue**

Wortsman et al. [71] published the first study to provide strong convincing evidence that VD (as a fat-soluble vitamin) may become sequestered within AT. In their study, the concentration of circulating cholecalciferol was similar between obese and lean groups at baseline, but the obese group had a significantly reduced response to the UVB intervention, resulting in a 57% lower serum cholecalciferol concentration postintervention, compared with the control group (lean). This suggested that the limitation in the obese group was the bioavailability of the synthesized cholecalciferol in circulation [71]. This sequestration theory is probably the most supported in the literature.

#### **3.5. Volumetric dilution**

Most recently, Drincic et al. [72] showed that body weight and body fat are inversely correlated with 25(OH)D levels across the spectrum of body weight ranging from normal to obese. This inverse association is related to the greater volume of distribution for both VD3 and 25(OH)D in tissue mass. They suggested that simple volumetric dilution is the most thrifty explanation for the low VD status in obesity. A hyperbolic model best explains the lower 25(OH)D values in obesity, and when serum 25(OH)D values was adjusted for body weight, difference between obese and normal subjects disappeared. These authors went on to recommend that the VD dosing for treatment of VDD in obesity should be based on body weight, for example, "one size does not fit all" [72].

Overall, although these are the five most commonly suggested mechanisms, the latter two theories have more robust evidences available. The strong evidence presented for the sequestration and volumetric dilution hypotheses, and more importantly, a lack of contradictory evidence for either, suggest that they are the most probable, independently or in combination, to explain the low VD status widely reported in obesity.
