Elsevier

Nutrition Research

Volume 53, May 2018, Pages 51-60
Nutrition Research

Dysregulated 1,25-dihydroxyvitamin D levels in high-fat diet–induced obesity can be restored by changing to a lower-fat diet in mice

https://doi.org/10.1016/j.nutres.2018.03.008 Get rights and content

Abstract

Altered regulation of vitamin D metabolites, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D (1,25[OH]2D), was observed in high-fat diet (HFD)–induced obesity. We hypothesized that these HFD-induced changes in vitamin D metabolism would be reversed by decreasing fat mass through dietary intervention. Four-week-old C57BL/6J mice were assigned to 1 of 3 experimental diet groups: (1) the LL group was fed a control diet for 31 weeks, (2) the HH group was fed an HFD for 31 weeks, and (3) the HL group was fed HFD for 15 weeks then switched to the control diet for the remaining 16 weeks. The fat mass of the HL group decreased by 15% from the 14th to the 30th week. Serum 1,25(OH)2D level was significantly higher in the HH group than the LL group, whereas that of the HL group was intermediate to the 2 groups. Serum parathyroid hormone and renal 1-hydroxylase (Cyp27b1) mRNA levels, which are known to stimulate renal 1,25(OH)2D production, were significantly higher in the HH group than the LL group. After losing fat mass, the HL group had significantly lower renal Cyp27b1 mRNA levels than the HH group. No differences were found in serum 25-hydroxyvitamin D levels and mRNA levels of hepatic 25-hydroxylases. In adipose tissue, mRNA levels of 25-hydroxylase and vitamin D receptor were elevated in parallel to the adiposity. In conclusion, serum 1,25(OH)2D levels were closely associated with body adiposity, and reducing fat mass by changing to a lower-fat diet can reverse this obesity-associated increase in circulating 1,25(OH)2D levels.

Introduction

Obesity is often associated with vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] concentrations below 20 ng/mL or 50 nmol/L) in human populations [1]. According to a recent meta-analysis study [2], the prevalence of vitamin D deficiency in obese humans was 35% higher than that in nonobese humans. It has been suggested that sequestration of vitamin D in adipose tissue due to its lipophilic nature contributes to an inverse relationship between serum 25(OH)D and body mass index [3]. Negative feedback or impaired hepatic 25(OH)D synthesis resulting from elevated 1,25-dihydroxyvitamin D (1,25[OH]2D) has also been suggested as a mechanism for this inverse relationship [4], [5]. Recently, a simple volumetric dilution model has been proposed to explain the low vitamin D status in obese humans [6]. However, the mechanism(s) of decreased vitamin D in obesity has not yet been elucidated.

In kidney, 1-hydroxylase converts 25(OH)D into bioactive 1,25(OH)2D which has, in addition to its classical roles on calcium homeostasis, regulatory effects on cell proliferation and differentiation, inflammation, glucose homeostasis, and adipogenesis [7]. Renal 1,25(OH)2D production is tightly regulated by parathyroid hormone (PTH) [8], fibroblast growth factor 23 (FGF23) [9], and 1,25(OH)2D itself [10] under normal physiological conditions. However, abnormally regulated serum 1,25(OH)2D in obese individuals has been observed. Bell et al [11] and Grethen et al [12] reported that serum 1,25(OH)2D concentrations were elevated (along with PTH) and serum 25(OH)D levels were decreased in obese humans. Bell et al [11] suggested that secondary hyperparathyroidism induced by obesity would account for the increased renal 1,25(OH)2D production. In contrast, a negative association between 1,25(OH)2D and body mass index [13] or decreased serum 1,25(OH)2D levels in obese humans [14] have been reported by others. These authors rationalized that serum 1,25(OH)2D levels were more likely to vary according to its substrate, namely, 25(OH)D, availability. However, the discrepancies between studies are not well understood because there are very limited number of studies that have specifically investigated altered 1,25(OH)2D metabolism in obesity. Although serum 25(OH)D concentration is considered as an indicator of vitamin D status, understanding -of changes in 1,25(OH)2D metabolism is necessary because abnormal regulation of 1,25(OH)2D, biologically active vitamin D metabolite, associated with obesity has been reported. Furthermore, it has been proposed that 1,25(OH)2D can regulate energy expenditure and adipogenesis in adipose tissue by binding to vitamin D receptor (VDR).

Whether altered vitamin D metabolism in obese individuals could be reversed by weight loss has been investigated in several studies. However, the effects of weight loss resulting from diet restriction on vitamin D status remain inconclusive. A significant weight loss was achieved by bariatric surgery, but the preoperative vitamin D deficiency persisted, and the serum 25(OH)D improved in only a small subset of obese patients [15], [16]. After participating in a weight loss program for 1 year, circulating 25(OH)D levels of 103 obese men increased by 26% along with a decrease in visceral adiposity volume [17]. A significant increase in 25(OH)D and decrease in PTH levels were reported in obese patients with knee osteoarthritis whose body weights were decreased by 14.0 kg (11.0 kg as fat) following 16 weeks of energy restriction [18]. However, an 8.5-kg loss of body weight (7.0% fat loss) resulted in a significant decrease in serum PTH level with no significant change to serum 25(OH)D [19]. Unfortunately, most studies reporting obesity-related changes in vitamin D status have not reported serum 1,25(OH)2D levels, and few reports exist in the literature relating changes in serum 1,25(OH)2D levels to weigh/fat loss.

In the current study, we investigated the effects of diet-induced obesity and subsequent reduction of fat mass on vitamin D metabolism in mice. We hypothesized that altered vitamin D metabolism in obese mice fed high-fat diet (HFD) could be reversed by a decrease in adiposity by switching the diet to a lower-fat diet. To test this hypothesis, reduction of fat mass was achieved in HFD-induced obese mice by changing the diet from high fat to low fat. Vitamin D status was evaluated by measuring serum 25(OH)D and 1,25(OH)2D levels. The expression of genes related to vitamin D metabolism in liver, kidney, and adipose tissue was compared between mice fed the different diets.

Section snippets

Animals and diets

Four-week-old female C57BL/6J mice were purchased from the Jackson Laboratory (Bar Harbor, ME, USA) and individually housed at the animal care facility at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. Mice were maintained in hepa-filtered ventilated cages located in AAALAC-accredited facilities with an environmentally controlled atmosphere (22°C, 45% relative humidity, and a 12/12-hour light/dark cycle [07:00 on]). After 5 days of acclimation with a control

Body weight, fat mass, and dietary intake

At the 15th week, average body weight and fat mass of HL and HH groups were significantly higher than those of LL group. At the 31st week, body weights and body fat mass were significantly different among the groups, with the body weight of mice in the HL group being intermediate to that of the LL and HH groups. The HL group did not gain weight after switching from an HFD to the low-fat control diet (40.9 ± 1.8 g at the 15th week and 40.6 ± 1.4 g at the 31st week). The body weight of the LL and

Discussion

In the current study, we demonstrated that changes in vitamin D metabolism associated with HFD-induced obesity could be reversed by reduction of fat mass by switching diet from the HFD to a lower-fat diet. After 16 weeks on a low-fat diet, obese mice produced by ad libitum feeding of an HFD had a significant decrease in body adiposity. This reduction of fat mass led to a partial restoration of the regulatory pathway of circulating 1,25(OH)2D as demonstrated by downregulated serum 1,25(OH)2D

Acknowledgment

This research was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2015R1D1A1A01059679) and USDA contract #58-1950-0-014. The authors have no conflicts of interest to report.

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