Impaired Release of Vitamin D in Dysfunctional Adipose Tissue

New Cues on Vitamin D Supplementation in Obesity

Andrea Di Nisio; Luca De Toni; Iva Sabovic; Maria Santa Rocca; Vincenzo De Filippis; Giuseppe Opocher; Bruno Azzena; Roberto Vettor; Mario Plebani; Carlo Foresta


J Clin Endocrinol Metab. 2017;102(7):2564-2574. 

In This Article

Abstract and Introduction


Context: Vitamin D accumulates in adipose tissue (AT), and vitamin D deficiency is frequent in obesity.

Objective: We hypothesize that trafficking of vitamin D is altered in dysfunctional AT.

Design, Patients, Settings: Fifty-four normal-weight and 67 obese males were recruited in a prospective study and randomly assigned to supplementation with 50 μg/wk 25-hydroxyvitamin-D3 or 150 μg/wk vitamin D3 for 1 year, raising dosage by 50% if vitamin D sufficiency [serum 25-hydroxyvitamin-D3>50 nmol/L], was not achieved at 6 months; 97 subjects completed the study.

Methods: Vitamin D3 and 25-hydroxyvitamin-D3 were quantified by HPLC-MS in control and insulinresistant (IR) 3T3-L1 cells and subcutaneous AT (SAT) from lean and obese subjects, incubated with or without adrenaline; expression of 25-hydroxylase (Cyp27a1), 1α-hydroxylase (Cyp27b1), and vitamin D receptor (Vdr) was analyzed by real-time polymerase chain reaction.

Results: In IR adipocytes, uptake of D3 and 25-hydroxyvitamin-D3 was higher, but, after adrenaline stimulation, the decrement in D3 and 25-hydroxyvitamin-D3 was stronger in control cells, which also showed increased expression of Cyp27a1 and Cyp27b1 and higher levels of 25-hydroxyvitamin-D3. In SAT from obese subjects, adrenaline-induced release of D3 and 25-hydroxyvitamin-D3 was blunted; in both IR cells and obese SAT, protein expression of β 2-adrenergic receptor was reduced. Supplementation with 25-hydroxyvitamin-D3 was more effective in achieving vitamin D sufficiency in obese, but not in normal weight subjects.

Conclusion: Dysfunctional AT shows a reduced catecholamine-induced release of D3 and 25-hydroxyvitamin-D3 and altered activity of vitamin D–metabolizing enzymes; for these reasons supplementation with 25-hydroxyvitamin-D3 is more effective in obese individuals.


Vitamin D is a lipophilic hormone playing a key role in bone metabolism and calcium homeostasis,[1] and it is also involved in many other pathological processes[2] commonly linked with obesity. To achieve its biological function, 1,25-dihydroxyvitamin D3 requires two sequential hydroxylation steps from vitamin D3 catalyzed by 25-hydroxylase and 1α-hydroxylase. The concentration of the preactivated vitamin D, 25-hydroxyvitamin-D [25(OH)D], is considered the most reliable marker of vitamin D status.

The high prevalence of vitamin D deficiency in obese subjects[3] suggests that adipose tissue (AT) has a major role in the body distribution of vitamin D, but the causal relationship between obesity and low levels of circulating 25(OH)D has not been completely elucidated yet. To this regard, as suggested from studies in humans and animal models receiving high doses of oral vitamin D3,[4,5] it has been proposed that vitamin D, being fat soluble, could be sequestered in body fat depots, leading to lower bioavailability in the obese state.[5,6] An alternative hypothesis considers low serum 25(OH)D in obese as a result of volumetric dilution of vitamin D in the large adipose stores.[7]

Taken together, these results suggest that body mass index (BMI) should be taken into account when determining the vitamin D intake required for optimal status.[8,9] Moreover, although fat depots mainly consist of cholecalciferol, 25(OH)D is widely distributed in many tissues, with the highest concentrations in serum.[10] On these bases, we can understand why orally administrated vitamin D3 has a lower impact on 25(OH)D levels in obese subjects,[5,11] as it is markedly stored in AT.[12]

This scenario is further complicated by the altered molecular phenotype featuring AT in obesity-induced inflammation and insulin resistance.[13] The catecholamine and natriuretic peptide lipolytic resistance in both obese patients[14] and insulin-resistant (IR) adipocytes[15] may lead to a reduced release of vitamin D from AT. Indeed, not only vitamin D is stored in AT, but it is slowly released into circulation.[16] However, the mechanisms controlling the deposition and release of vitamin D from AT are still unknown.[17] It is likely that, because vitamin D is a fat-soluble secosteroid, it is subjected to the same pathway of cathecolamine-induced lipolysis observed for cholesterol.[18]

Moreover, both human and murine adipocytes express vitamin D–metabolizing enzymes [reviewed by Ding et al.[19]], suggesting that AT not only passively accumulates vitamin D, but also changes its metabolism in obesity.

Despite the well-established relationship between obesity and low vitamin D, few experimental studies have investigated the biological processes involved in vitamin D metabolism in AT, with conflicting results.[10,20]

We hypothesized that AT is capable of vitamin D up-take, but in the pathological state the lipolysis-mediated release of vitamin D is impaired, concomitantly with an altered enzymatic machinery. On these bases, we would expect that 25-hydroxyvitamin-D3 rather than vitamin D3 is a more adequate supplementation in obese subjects. Thus, we investigated the following: (1) whether D3 and 25(OH)D are differentially accumulated and released after adrenaline-induced lipolysis in control and IR 3T3-L1 adipocytes; (2) whether vitamin D–metabolizing enzymes are impaired in IR adipocytes; (3) the concentrations of vitamin D3 and 25(OH)D in ex vivo subcutaneous AT (SAT) from normal weight and obese subjects before and after lipolytic stimulation; and (4) whether supplementation with 25(OH)D is more effective in achieving vitamin D sufficiency in obese subjects, compared with vitamin D3.