Abstract
Low circulating levels of total and free 25-hydroxyvitamin D (25(OH)D) indicative of vitamin D status have been associated with obesity in humans. Moreover, obesity is thought to play a causal role in the reduction of 25(OH)D levels, and several theories have been put forward to explain this relationship. Here we tested the hypothesis that obesity disrupts vitamin D homeostasis in key organs of vitamin D metabolism. Male C57BL6 mice were fed for 7 or 11 weeks on either a control diet (control, 10% energy from fat) or a high-fat diet (HF, 60% energy from fat) formulated to provide equivalent vitamin D3 intake in both groups. After 7 weeks, there was a transient increase of total 25(OH)D together with a significant decrease of plasma vitamin D3 that could be related to the induction of hepatic genes involved in 25-hydroxylation. After 11 weeks, there was no change in total 25(OH)D but a significant decrease of free 25(OH)D and plasma vitamin D3 levels. We also quantified an increase of 25(OH)D in adipose tissue that was inversely correlated to the free 25(OH)D. Interestingly, this accumulation of 25(OH)D in adipose tissue was highly correlated to the induction of Cyp2r1, which could actively participate in vitamin D3 trapping and subsequent conversion to 25(OH)D in adipose tissue. Taken together, our data strongly suggest that the enzymes involved in vitamin D metabolism, notably in adipose tissue, are transcriptionally modified under high-fat diet, thus contributing to the obesity-related reduction of free 25(OH)D.
Highlights
Vitamin D is a secosteroid hormone that plays key roles in phosphocalcium homeostasis and bone metabolism [1] and has many other biological functions [2]
Body weight, liver weight and adiposity index were increased in the high-fat diet-fed mice (HF) group at 7 weeks and at 11 weeks compared to the control diet (Table 2 and Supplemental Figure 1)
The primary objective of this study was to use a murine model to demonstrate the impact of obesity on vitamin D metabolism, the effect on plasma free 25(OH)D levels as recently described in humans [14], and bring mechanistic evidence by studying gene expression in the main organs involved in vitamin D metabolism
Summary
Vitamin D is a secosteroid hormone that plays key roles in phosphocalcium homeostasis and bone metabolism [1] and has many other biological functions [2]. The native vitamin D has to be converted in the liver into 25-hydroxyvitamin D (25(OH)D), in a first hydroxylation step catalyzed by 4 enzymes (CYP2R1, CYP27A1, CYP2J6 and CYP3A11) [5]. A second hydroxylation step catalyzed by CYP2B1 in the kidney produces 1,25-dihydroxyvitamin D (1,25(OH)2D), the active form of cholecalciferol, which is a potent activator of the vitamin D receptor (VDR) [6]. Vitamin D status is classically reflected by total plasma 25(OH)D concentration, which represents the sum of free 25(OH)D and 25(OH)D bound to vitamin D binding protein (DBP, encoded by the Gc gene) and albumin [8, 9]. Vitamin D status is impacted by a number of physio-pathological parameters, including obesity which is classically associated to a decrease of total 25(OH)D [10, 11]. Plasma 25(OH)D levels are inversely correlated to all parameters of obesity, including BMI, fat mass and waist circumference [12, 13]
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