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The Journal of Clinical Endocrinology and Metabolism logoLink to The Journal of Clinical Endocrinology and Metabolism
. 2024 Nov 12;110(8):2215–2224. doi: 10.1210/clinem/dgae775

Weight Loss Induces Changes in Vitamin D Status in Women With Obesity But Not in Men: A Randomized Clinical Trial

Rune Holt 1,2, Joachim Holt 3, Mads Joon Jorsal 4, Rasmus Michael Sandsdal 5, Simon B K Jensen 6, Sarah Byberg 7, Christian Rimer Juhl 8, Julie Rehné Lundgren 9, Charlotte Janus 10, Bente Merete Stallknecht 11, Jens Juul Holst 12,13, Anders Juul 14,15,16, Sten Madsbad 17, Martin Blomberg Jensen 18,19, Signe Sørensen Torekov 20,✉
PMCID: PMC12261087  PMID: 39530599

Abstract

Context

Obesity is associated with low vitamin D status -, and recent studies have suggested a difference in vitamin D metabolism between females and males.

Objective

The aim of this study was to investigate the effects of weight loss on vitamin D status in individuals with obesity, and secondarily, whether vitamin D metabolism differs between women and men.

Methods

Secondary analysis from a randomized placebo-controlled trial, designed to investigate the efficacy of 52 weeks of treatment with either liraglutide, exercise, or both combined compared with placebo on weight loss maintenance after an 8-week low-calorie diet-induced weight loss in 195 individuals with obesity (body mass index 32-43 kg/m2).

Results

The low-calorie diet-induced weight loss resulted in an increase in serum 25-hydroxyvitamin D (25(OH)D) in both women and men [12 nmol/L (95% confidence interval [CI] 9-15) and 13 nmol/L (95% CI 8-17); P < .001 for both]. Women who experienced a further weight loss during the 52 weeks of intervention had an increase in serum 25(OH)D compared with women regaining weight [14 nmol/L (95% CI 6-22); P = .001]. Interestingly, women experiencing further weight loss at week 52 had a lower serum 25(OH)D at baseline compared with women regaining weight [54 nmol/L (SD 19) vs 70 nmol/L (SD 25), P < .001.]

Conclusion

Weight loss induced by a low-calorie diet resulted in an increase in serum 25(OH)D in both women and men. Only in women, further weight loss had an additional beneficial impact on vitamin D. Additionally, initial low serum 25(OH)D was associated with successful weight loss maintenance in women but not men.

Trial registration

ClinicalTrials.gov number: NCT04122716

Keywords: vitamin D, obesity, weight loss, sex differences, glucagon-like peptide-1, GLP-1 receptor agonist

The prevalence of obesity is increasing worldwide (1) and is associated with diseases such as hypertension, type 2 diabetes, and cardiovascular diseases as well as years of life lost (2, 3). Nonpharmacological modification of diet and increase in exercise is important for the treatment of obesity, though these interventions have failed to result in long-term weight loss (4). Within the last decade incretin-based treatments, such as liraglutide, semaglutide, and tirzepatide, have been shown to induce sustainable weight loss and are currently used in the treatment of obesity (5, 6).

Vitamin D is a steroid hormone with pleiotropic effects. Besides its essential influence on bone health and calcium homeostasis, vitamin D deficiency has been associated with obesity, metabolic disorders, and diabetes (7). Vitamin D is synthesized de novo from cholesterol when the skin is exposed to UVB radiation but can also be absorbed in the intestines from food or supplements. Vitamin D3 (cholecalciferol) is hydroxylated in the liver to 25-hydroxyvitamin D (25(OH)D) and subsequently in the kidney to the active hormone, 1,25-dihydroxyvitamin D, which exerts its biological effects via the vitamin D receptor (VDR) (7). One of the strongest regulators of the activation of 25(OH)D to 1,25-dihydroxyvitamin D is PTH. The main function of PTH is to maintain a stable serum calcium concentration via enhancing calcium from bone resorption and renal reabsorption (8).

Low serum 25(OH)D concentration is associated with obesity (9). Multiple hypotheses have been proposed to explain the negative association including volumetric dilution, sequestration of vitamin D in adipose tissue, and limited sun exposure (9). Vitamin D supplementation is not associated with weight loss (9); however, weight loss may have a beneficial effect on vitamin D status, indicating that obesity directly affects vitamin D metabolism. This is supported by studies showing that obesity represses the enzymatic conversion of cholecalciferol to 25(OH)D (10, 11).

The vitamin D regulating enzymes [24-hydroxylase (CYP24A1), 1-alpha-hydroxylase (CYP27B1), and 25-hydroxylase (CYP2R1)] and the VDR are all expressed in adipocytes, indicating vitamin D may directly affect adipose tissue; however, results regarding the overall effects of vitamin D on adipose tissue are inconclusive (12, 13). Interestingly, both animal and human studies have indicated a potential difference in vitamin D metabolism between the sexes (14-17), as the expression of the vitamin D activating (CYP2R1 and CYP27B1) and inactivating enzymes (CYP24A1) and the VDR may differ (14). Differences in sex hormone levels, body fat distribution, and regulation of adipose tissue between females and males may contribute to the sex differences in vitamin D metabolism (14, 18, 19).

This study is a secondary analysis of a placebo-controlled randomized clinical trial, designed to investigate the effects of one year intervention with a glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide and/or exercise against placebo on weight loss maintenance in individuals with obesity without diabetes after an 8-week low-calorie diet. We hypothesized that weight loss influences vitamin D status in individuals with obesity and that vitamin D metabolism varies between women and men.

Methods

Study Design

We analyzed data from a randomized double-blind, placebo-controlled clinical trial (the S-LiTE trial) that was carried out at the University of Copenhagen and the Department of Endocrinology at Hvidovre Hospital, Denmark. The intervention period ran from August 2016 to November 2019. The study protocol was published previously (20). The study was approved by the local ethics committee of the Capital Region of Denmark (H-16027082), the Danish Data Protection Agency, and the Danish Medicines Agency (EudraCT Number: 2015-005585-32) and was registered at ClinicalTrials.gov, number NCT04122716. The primary endpoint was change in body weight and was previously published, and the sample size was calculated based on this (21). This study presents secondary analyses of changes in serum 25(OH)D and exploratory analyses of changes in serum PTH and calcium.

Participants

The full list of inclusion and exclusion criteria is available in the published study protocol (20). In short, adults (age 18-65 years) with obesity were eligible to participate in the study with the following criteria: body mass index (BMI) 32 to 43 kg/m2 and not having diabetes. Self-reported vitamin D supplementation was noted at baseline (week -8). Participants with a serum 25(OH)D < 50 nmol/L were recommended vitamin D supplementation. Informed written consent was obtained from all participants before inclusion in the study. Sex assigned at birth was self-reported by participants and registered by a medical doctor.

Interventions

Two hundred fifteen participants were included and asked to follow a low-calorie diet (800 kcal/day) for 8 weeks, where all food was replaced with 4 meal replacements per day with the aim of achieving >5% body weight loss. Each meal replacement contained approximately 200 kcal, 1.7 to 3.8 µg of cholecalciferol, and 200 to 250 mg of calcium. Overall, 195 of the participants completed the low-calorie diet and lost >5% of body weight and were subsequently equally randomized and stratified according to sex assigned at birth and age to 52 weeks of either (1) placebo with habitual physical activity (n = 49), (2) placebo and exercise intervention (n = 48), (3) liraglutide (3.0 mg/day) with habitual physical activity (n = 49), or (4) liraglutide (3.0 mg/day) and exercise intervention (n = 49). The aim of the exercise intervention was to achieve the World Health Organization-recommended minimum physical activity level of 150 minutes of moderate intensity physical activity per week or 75 minutes of vigorous-intensity physical activity per week or a combination thereof. The medication was self-administered and initiated at a dose of 0.6 mg/day followed by weekly escalations of 0.6 mg/day until reaching 3.0 mg/day or the highest tolerable dose. The participants and study personnel were blinded regarding the medication. A detailed description of the interventions can be found in the published protocol (20).

Outcomes

All outcomes were evaluated at 3 timepoints: at baseline (week -8) before the low-calorie diet, at randomization (week 0), and after 52 weeks. Serum 25(OH)D, PTH, total calcium, albumin, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, glycated hemoglobin (HbA1c), and serum insulin were measured on the COBAS 9000 system at the Department of Clinical Biochemistry, Hvidovre Hospital, Denmark. Fasting glucose was measured with a YSI model 2300 STAT plus (YSI Inc.). Leptin was analyzed with a radioimmunoassay kit (Merck Millipore, RRID:AB_2756879), and adiponectin was analyzed with ELISA (BioVendor R&D, RRID:AB_2909450). Body composition was assessed with full-body dual-energy x-ray absorptiometry scans (Hologic, Discovery A) after an overnight fast. Fat mass was assessed with the scanner software (APEX System Software Version 3.4.2). Reports on weight loss, glucose, insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), HbA1c, cholesterol, lipids, metabolic syndrome, bone health, and high-sensitivity c-reactive protein have previously been published (21-24).

Statistical Analyses

Descriptive statistics are presented as mean with SD, median with interquartile range, or mean with 95% confidence interval (CI). Distribution of data was visually inspected for normality and changes within groups were analyzed with a paired sample t-test, and differences between groups were analyzed with an independent t-test on an ordinal scale for normally distributed data and log-scale for nonnormally distributed data. Categorical variables were analyzed using the chi-square test. General linear regression was used to investigate associations between changes in serum 25(OH)D and changes in body weight. An analysis of covariance was used to investigate differences in serum 25(OH)D at baseline between women with a weight loss and weight gain. A serum 25(OH)D concentration <50 nmol/L is associated with an unfavorable impact on the skeleton (25). Though some data has suggested a higher threshold (25), we define vitamin D sufficiency as serum 25(OH)D concentration >50 nmol/L in accordance with the Danish health authorities (26). Serum albumin-corrected calcium (alb.corr. calcium) was calculated as: [serum total calcium (mmol/L) + 0.02 × (40—serum albumin (g/L)], regardless of the serum albumin concentration. The HOMA-IR index, a measure of insulin resistance, was calculated by multiplying fasting insulin and glucose divided by 22.5. Adjustment for multiple comparisons was not made due to the exploratory nature of the analyses. No observations were excluded. A P-value <.05 was considered statistically significant. Results are visualized in GraphPad Prism v10.1.0, and all statistical analyses are performed in IBM SPSS Statistics version 28.

Results

More women than men participated in the trial (63% vs 37%). As expected, women had a lower height and weight and a higher body fat mass than men. The BMI was similar between the sexes. Characteristics of the participants at baseline before the low-calorie diet are shown in Table 1.

Table 1.

Baseline (week -8) characteristics according to sex

Mean (SD) (n) Womena (n) Mena P
Included (%) 135 63 80 37 —
Age (years) 135 42 (12) 80 42 (13) .852
Height (cm) 135 167 (6) 80 181 (7) <.001
Weight (kg) 135 102 (10) 80 122 (13) <.001
BMI (kg/m2) 135 37 (3) 80 37 (3) .628
Body fat mass in kg 135 46 (7) 78 43 (8) <.001
Body fat mass in % 135 45 (4) 78 35 (4) <.001
Treated with liraglutideb (%) 62 50 36 51 .925
Season of inclusionc (%) 57 47 34 49 .774
Self-reported vitamin D suppl. (%) 23 17 3 4 .003
Vitamin D sufficientd (%) 82 62 37 47 .036
25(OH)D (nmol/L) 133 60 (24) 79 48 (21) <.001
PTH (pmol/L) 133 5.9 (2.1) 79 5.9 (2.1) .941
Total calcium (mmol/L) 133 2.31 (0.08) 80 2.34 (0.07) .008
Alb.corr. calcium (mmol/L) 103 2.39 (0.08) 60 2.35 (0.07) .004
Albumin (g/L) 103 36 (3) 60 40 (2) <.001
Adiponectin (µg/mL) 103 8.5 (3.3) 61 6.5 (2.4) <.001
Leptin (ng/mL) 104 67 (33) 61 35 (19) <.001
Leptin/adiponectin ratio 103 9.0 (6.8) 61 6.1 (4.0) .003
Fasting insulin (pmol/L) 99 91 (53) 59 110 (54) .028
HbA1c (mmol/mol) 132 36 (4) 79 36 (4) .556
HOMA-IR index 99 3.6 (2.2) 59 4.6 (2.5) .010
HDL (mmol/L) 132 1.3 (0.3) 80 1.1 (0.3) <.001
LDL (mmol/L) 129 3.0 (0.8) 80 3.1 (0.9) .885
Triglycerides (mmol/L) 132 1.2 [0.9-1.6] 80 1.4 [1.0-2.0] .031
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Data presented as mean (SD) or median [interquartile range] unless otherwise indicated.

P-value: Differences between groups were analyzed with an independent t-test on an ordinal scale for data presented with mean (SD) and log-scale for data presented with median [interquartile range]. For categorical variables, χ2 test was used. P-values < .05 are highligted with bolface.

Abbreviations: 25(OH)D, 25-hydroxyvitamin D; alb.corr, albumin-corrected; BMI, body mass index; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance; LDL, low-density lipoprotein.

a Sex assigned at birth.

b Randomized to liraglutide + exercise or liraglutide.

c Included from October to April.

d Vitamin D sufficient defined as a serum 25(OH)D > 50 nmol/L.

Vitamin D Status at Baseline

To explore potential differences in vitamin D metabolism between women and men, we divided participants according to sex assigned at birth (women vs men). At baseline, women had a higher serum 25(OH)D concentration compared with men [60 nmol/L (SD 24) vs 48 nmol/L (SD 21); P < .001]. More women were vitamin D sufficient (62% vs 47%; P = .036) and reported taking vitamin D supplements at baseline (17% vs 4%; P = .003) compared with men (Table 1). There was no difference in age, BMI, or season of inclusion between women and men. Adjusting for vitamin D supplementation, season of inclusion, BMI, and age did not affect the differences in serum 25(OH)D at baseline between women and men (59 nmol/L vs 48 nmol/L; P < .001). Women had a lower total serum calcium compared with men [2.31 mmol/L (SD 0.08) vs 2.34 mmol/L (SD 0.07); P = .004], although a higher serum alb.corr. calcium [2.39 mmol/L (SD 0.08) vs 2.35 mmol/L (SD 0.07); P = .004] as women had a lower serum albumin concentration [36 g/L (SD 3) vs 40 g/L (SD 2); P < .001]. There was no difference in serum PTH. The glucose and lipid profiles are also presented in Table 1 and have previously been described (21). Women had a lower serum insulin, triglycerides, and HOMA-IR and a higher serum HDL concentration, adiponectin, leptin, and leptin/adiponectin ratio compared with men, whereas there were no differences in serum HbA1c or LDL (Table 1).

Effects of Low-calorie Diet-induced Weight Loss on Vitamin D Status

The 8-week low-calorie diet resulted in 11% weight loss in women [102 kg (95% CI 100-104) vs 91 kg (95% CI 90-93); P < .001] and 14% weight loss in men [122 kg (95% CI 120-125) vs 106 kg (95% CI 103-109); P < .001] (Table 2). The average weight loss in percentages was higher in men compared with women.

Table 2.

Effects of an 8-week low-calorie diet-induced weight loss on vitamin D status in women and men

Mean (±95% CI) Week 0 Differences
(Week 0 vs -8)		 P
Womena
 Weight (kg) 91 (90-93) −11 (−12/−11) <.001
 Vitamin D sufficientb (%) 82 20 <.001
 25(OH)D (nmol/L) 72 (68-77) 12 (9-15) <.001
 PTH (pmol/L) 5.4 (5.1-5.7) −0.4 (−0.7/−0.3) <.001
 Total calcium (mmol/L) 2.37 (2.36-2.39) 0.06 (0.04-0.07) <.001
 Alb.corr. calcium (mmol/L) 2.41 (2.39-2.42) 0.01 (−0.00-0.03) .059
Mena
 Weight (kg) 106 (103-109) −17 (−18/−15) <.001
 Vitamin D sufficientb (%) 68 21 <.001
 25(OH)D (nmol/L) 63 (58-68) 13 (8-17) <.001
 PTH (pmol/L) 5.0 (4.6-5.3) −0.9 (−1.2/−0.5) <.001
 Total calcium (mmol/L) 2.40 (2.39-2.42) 0.06 (0.04-0.08) <.001
 Alb.corr. calcium (mmol/L) 2.39 (2.37-2.41) 0.03 (0.02-0.05) <.001
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Data presented as mean ±95% CI, unless otherwise indicated. Differences: Absolute changes from baseline (week -8) to week 0.

P-value: Changes from baseline (week-8) to week 0 were assessed by a paired sample t-test, except for vitamin D sufficiency where χ2 test was used. P-values < .05 are highligted with boldface.

Abbreviations: 25(OH)D, 25-hydroxyvitamin D; alb.corr, albumin-corrected; CI, confidence interval.

a Sex assigned at birth.

b Changes in percentage point.

The low-calorie diet-induced weight loss had a significant impact on the calciotropic system in both women and men. Women had an average increase in serum 25(OH)D of 12 nmol/L (95% CI 9-15; P < .001) like men who had an average increase of 13 nmol/L (95% CI 8-17; P < .001). However, women tended to have a higher increase in serum 25(OH)D compared with men [14 nmol/L (95% CI 11-18) vs 9 nmol/L (95% CI 4-14); P = .086] when adjusting for baseline serum 25(OH)D and body weight. In women, the decrease in body weight from baseline to week 0 was associated with a corresponding increase in serum 25(OH)D [β: −1.4 (95%CI −2.6 to −0.3); P = .016]. Moreover, women had a 0.4 pmol/L decrease in serum PTH [5.9 (95% CI 5.5-6.3) vs 5.4 (95% CI 5.1-5.7); P < .001] whereas men had a decrease of 0.9 pmol/L [5.9 pmol/L (95%CI 5.5-6.4) vs 5.0 pmol/L (95% CI 4.6-5.3); P < .001], significantly different from women [−0.4 pmol/L (95% CI −0.7 to −0.2) vs −0.9 pmol/L (95% CI −1.2 to −0.5); P = .038]. However, in a model adjusting for baseline serum PTH and body weight, the difference between the sexes disappeared [−0.5 pmol/L (95% CI −0.8 to −0.3) vs −0.7 pmol/L (95% CI −1.0 to −0.4); P = .430].

The low-calorie diet-induced weight loss resulted in an increase in serum calcium in both women and men, though only men had an increase in serum alb.corr. calcium (Table 2). The changes in serum calcium and alb.corr. calcium were similar between women and men.

Effects of Changes in Body Weight on Vitamin D Status After 1 Year

To investigate the long-term impact of changes in body weight on vitamin D status, we further grouped participants according to changes in weight at week 52 compared to week 0 (weight loss vs weight gain), regardless of randomization (Fig. 1A and 1E). Women with a weight loss had no change in serum 25(OH)D at week 52 compared with week 0, whereas women who regained weight had a decrease of 8 nmol/L (95% CI -14 to -3; P = .001), and the changes in serum 25(OH)D from week 0 to week 52 were different in women with a weight loss vs weight gain [Δ25(OH)D: 14 nmol/L (95% CI 6-22); P = .001] (Fig. 1B). There was no change in serum 25(OH)D at week 52 compared with week 0 in men with a weight loss or weight gain, respectively, nor a difference between the groups (Fig. 1F).

Figure 1.

Figure 1.

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Changes in weight, serum 25(OH)D, PTH, and albumin-corrected calcium during the trial in women and men according to weight loss or weight gain. (A + E) Changes in weight; (B + F) changes in serum 25(OH)D; (C + G) changes in serum PTH; (D + H) changes in serum albumin-corrected calcium. During the 8-week low-calorie diet, changes from baseline to week 0 are presented for the total cohort (black line) and changes from week 0 to week 52 are divided according to achieved weight loss (red line) or weight gain (blue line) in women (A-D) and in men (E-H). Data are presented as mean ± 95% confidence interval. Changes within groups from week 0 to week 52 are assessed by a paired sample t-test and significant changes are illustrated with a horizontal red or blue line and asterisk. Difference in change between groups at week 52 is assessed by an independent t-test, and significant differences are illustrated with a vertical black line and asterisk. *P < .05, **P < .01, and ***P < .001. Abbreviations: 25(OH)D, 25-hydroxyvitamin D.

Women with a weight loss had a decrease of 0.8 pmol/L (95% CI 0.5-1.1; P < .001) in serum PTH at week 52 compared with week 0, whereas women with a weight gain had no changes in serum PTH. The changes in serum PTH from week 0 to week 52 were different between women with a weight loss vs weight gain [ΔPTH: −0.9 pmol/L (95%CI −1.4 to −0.4); P < .001] (Fig. 1C). There was no change in serum PTH at week 52 compared with week 0 in men with a weight loss or weight gain, respectively (Fig. 1G). Women with a weight loss had no change in serum alb.corr.calcium, whereas women with a weight gain had a decrease of 0.03 mmol/L (95% CI 0.00-0.05; P = .040) (Fig. 1D). Both men with a weight loss and a weight gain had a decrease in serum alb.corr. calcium [−0.04 mmol/L (95% CI −0.08 to −0.00; P = .032] and −0.06 mmol/L [95% CI −0.09 to −0.03; P < .001] (Fig. 1H). Interestingly, in women, changes in weight between week 0 and week 52 were associated with changes in serum 25(OH)D in the same period [β: −0.9 (95% CI −1.3 to −0.5); P < .001]. A similar association was not found in men (data not shown).

To investigate the potential impact of liraglutide on changes in the calciotropic system, we grouped participants according to randomization to liraglutide (liraglutide and liraglutide + exercise) and nonliraglutide (placebo and exercise). Overall, the results mimicked the effects of changes in body weight, though they were not as pronounced (Fig. 2).

Figure 2.

Figure 2.

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Changes in weight, serum 25(OH)D, PTH, and albumin-corrected calcium during the trial in women and men according to randomization to liraglutide or nonliraglutide. (A + E) Changes in weight; (B + F) changes in serum 25(OH)D; (C + G) changes in serum PTH; (D + H) changes in serum albumin-corrected calcium. During the 8-week low-calorie diet, changes from baseline to week 0 are presented for the total cohort (black line) and changes from week 0 to week 52 are divided according to randomization to liraglutide (red line) vs nonliraglutide (blue line) in women (A-D) and in men (E-H). Data are presented as mean ± 95% confidence interval. Changes within groups from week 0 to week 52 are assessed by a paired sample t-test, and significant changes are illustrated with a horizontal red or blue line and asterisk. Difference in change between groups at week 52 is assessed by an independent t-test and significant differences are illustrated with a vertical black line and asterisk. *P < .05, **P < .01, and ***P < .001. Abbreviations: 25(OH)D, 25-hydroxyvitamin D.

Vitamin D Status as a Marker of Weight Loss Maintenance

To explore baseline differences in the calciotropic system related to long-term changes in body weight, we divided participants by sex and additionally according to weight loss vs weight gain at week 52 compared to week 0.

Interestingly, women with a weight loss had a lower prevalence of vitamin D sufficiency and lower serum 25(OH)D concentration at baseline (week -8) compared with women with a weight gain [47% vs 81% and 54 nmol/L (SD 19) vs 70 nmol/L (SD 25); P < .001, for both] (Table 3). The difference in serum 25(OH)D was still highly significant after adjusting for relevant confounders such as season of inclusion, self-reported vitamin D supplementation at baseline, BMI, and age (54 nmol/L vs 69 nmol/L; P = .001). Furthermore, serum total calcium and alb.corr. calcium were lower in women with a weight loss compared with women with a weight gain [2.30 mmol/L (SD 0.06) vs 2.34 mmol/L (SD 0.09); P = .007 and 2.37 mmol/L (SD 0.06) vs 2.41 mmol/L (SD 0.10); P = .046]. There was no difference in serum PTH concentration between women with a weight loss vs weight gain.

Table 3.

Baseline (week-8) characteristics according to sex and changes in weight at week 52 vs week 0

Womena Mena
Mean (SD) (n) Weight loss (n) Weight gain P (n) Weight loss (n) Weight gain P
Age (years) 46 45 (11) 59 42 (12) .275 18 42 (15) 43 46 (11) .320
Weight (kg) 46 103 (10) 59 101 (10) .414 18 120 (114) 43 125 (12) .122
BMI (kg/m2) 46 37 (3) 59 37 (3) .382 18 36 (3) 43 38 (3) .144
Body fat mass, % 46 45 (3) 59 44 (4) .092 18 35 (4) 42 34 (4) .206
Android fat mass, % 45 47 (4) 58 45 (4) .077 18 42 (5) 41 41 (4) .229
Gynoid fat mass, % 45 45 (5) 58 45 (4) .419 18 35 (4) 41 32 (5) .071
Treated with liraglutideb, % 34 74 21 36 <.001 12 67 19 44% .109
Season of inclusionc (%) 20 44 31 53 .365 8 47 21 50 .838
Self-reported vitamin D suppl. (%) 6 13 12 20 .325 0 0 2 5 .352
Vitamin D sufficientd (%) 21 47 48 81 <.001 10 56 23 53 .883
25(OH)D (nmol/L) 45 54 (19) 59 70 (25) <.001 18 51 (23) 43 51 (19) .934
PTH (pmol/L) 45 5.6 (1.8) 59 5.6 (1.7) .974 18 5.8 (2.4) 43 5.7 (1.8) .885
Total calcium (mmol/L) 45 2.30 (0.06) 59 2.34 (0.09) .007 18 2.34 (0.08) 43 2.34 (0.07) .775
Alb.corr. calcium (mmol/L) 33 2.37 (0.06) 46 2.41 (0.10) .046 15 2.36 (0.07) 30 2.35 (0.08) .890
Albumin (g/L) 33 37 (3) 46 37 (3) .570 15 40 (3) 30 39 (2) .548
Adiponectin (µg/mL) 45 8.1 (3.1) 58 8.9 (3.4) .205 18 7.4 (2.6) 43 6.1 (2.3) .055
Leptin (ng/mL) 45 73 (33) 59 62 (33) .081 18 34 (21) 43 36 (18) .832
Leptin/adiponectin ratio 45 10.9 (8.5) 58 7.5 (4.5) .011 18 4.7 (2.5) 43 6.7 (4.3) .076
Fasting insulin (pmol/L) 45 91 (61) 54 91 (45) .985 18 98 (36) 41 116 (60) .234
HbA1c (mmol/mol) 45 36 (4) 58 36 (4) .914 17 35 (4) 43 37 (4) .227
HOMA-IR index 31 3.6 (2.5) 42 3.5 (1.9) .805 16 4.0 (1.6) 33 4.8 (2.8) .271
HDL (mmol/L) 44 1.3 (0.3) 59 1.4 (0.3) .043 18 1.2 (0.3) 43 1.1 (0.3) .702
LDL (mmol/L) 43 3.1 (0.9) 57 3.1 (0.8) .877 18 3.4 (0.8) 43 2.8 (0.7) .005
Triglycerides (mmol/L) 44 1.2 [0.8-1.4] 59 1.2 [0.9-1.6] .638 18 1.5 [0.9-1.9] 43 1.4 [0.9-2.0] .370
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Data presented as mean (SD) or median [interquartile range] unless otherwise indicated.

P-value: Differences between groups were analyzed with an independent t-test on an ordinal scale for data presented with mean (SD) and log-scale for data presented with median [interquartile range]. For categorical variables, χ2 test was used. P-values < .05 are highligted with boldface.

Abbreviations: 25(OH)D, 25-hydroxyvitamin D; alb.corr, albumin-corrected; BMI, body mass index; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance; LDL, low-density lipoprotein.

a Sex assigned at birth.

b Randomized to liraglutide + exercise or liraglutide.

c Included from October to April.

d Vitamin D sufficient defined as a serum 25(OH)D > 50 nmol/L.

Finally, women with a weight loss had a higher serum leptin/adiponectin ratio [10.9 (SD 8.5) vs 7.5 (SD 4.5); P = .011], lower serum HDL concentration [1.3 mmol/L (SD 0.3) vs 1.4 mmol/L (SD 0.3); P = .043] and tended to have a higher percentage of android fat mass [47% (SD 4) vs 45% (SD 4); P = .077] at baseline compared with women with a weight gain.

The only difference at baseline between men with a weight loss vs weight gain was serum LDL, as men with a weight loss had a higher serum LDL concentration compared with men with a weight gain [3.4 mmol/L (SD 0.8) vs 2.8 mmol/L (SD 0.7); P = .005] (Table 3).

The 8 weeks of low-calorie diet induced similar changes in weight and serum 25(OH)D between participants with an additional weight loss at week 52 compared with participants with a weight gain, in both women and men (data not shown).

Further, we divided women into 4 groups according to randomizations (placebo, exercise, liraglutide, and liraglutide + exercise) and investigated the differences in serum 25(OH)D at baseline in each group according to weight loss vs weight gain (Fig. 3). In all 4 groups, women with a weight loss tended to have a lower serum 25(OH)D concentration at baseline compared with women with a weight gain (Fig. 3). Notably, all 4 groups of women with a weight loss had comparable average serum 25(OH)D concentrations at baseline (52-55 nmol/L). When the same analyses were performed in men, no difference was found in baseline serum 25(OH)D between men with a weight loss vs weight gain (data not shown).

Figure 3.

Figure 3.

Open in a new tab

Serum 25(OH)D at baseline (week -8) in women according to randomization and weight loss vs weight gain at week 52. Data are presented for each individual and grouped according to randomization and weight loss (red dots) or weight gain (blue dots) at week 52 compared to week 0. Black line represents mean± 95% confidence interval (except for women randomized to placebo with a weight loss, where only mean is presented due to a low number of individuals). Difference between groups is assessed by an independent t-test. *P < .05 and **P < .01.

Discussion

This study shows that a low-calorie diet-induced weight loss in both women and men with obesity is associated with an increase in serum 25(OH)D and a decrease in serum PTH. Weight loss could be the causal factor in view of the recent finding that individuals with obesity need at least 50 µg cholecalciferol per day to maintain normal serum 25(OH)D levels (27), significantly more than supplied with during the low-calorie diet used in this study containing an average daily cholecalciferol concentration of ∼10 µg. This would support that the changes in serum 25(OH)D are caused by the changes in body weight rather than by exogenous vitamin D supplementation. Our findings are consistent with 2 systematic reviews investigating the relation between weight loss and vitamin D status, both concluding that weight loss induces an increase in serum 25(OH)D concentration (28, 29). The weight loss-induced increase in serum 25(OH)D concentration may be due to a volumetric dilution (30) or release of accumulated vitamin D from adipocytes (31). Moreover, it has been shown that obesity represses 25-hydroxylase, which converts cholecalciferol to 25(OH)D, in both the liver and adipose tissue, leading to a further aggravation of vitamin D status in individuals with obesity (10, 11). This obesity-induced suppression of 25-hydroxylase may be dynamic, as weight loss induced by gastric bypass surgery increases the expression of the 25-hydroxylase in human adipose tissue (11).

The effect of liraglutide on serum 25(OH)D and serum PTH was not as pronounced as the effects of weight loss vs weight gain, indicating that liraglutide does not directly influence the calciotropic system. Even though the GLP-1 receptor may be expressed in very small numbers on the calcitonin producing parafollicular C-cells of the thyroid gland in humans, a previous study found that liraglutide had no effect on serum calcitonin in humans (32).

Interestingly, a recent review has suggested possible sex differences in vitamin D metabolism (14), which our study supports as differences in serum 25(OH)D and serum PTH were only evident in women according to changes in body weight after 52 weeks. Additionally, we found that more women were vitamin D sufficient and had a higher serum 25(OH)D concentration and serum alb.corr. calcium at baseline compared with men, which is in line with a Norwegian study (17). Supporting a potential sex difference in vitamin D metabolism, Oczkowicz et al showed that female rats have a higher expression of 25-hydroxylase in the liver and kidney, indicating that female rats may have a higher conversion rate of cholecalciferol to 25(OH)D resulting in a higher serum 25(OH)D concentration (15). Furthermore, they found tissue specific sex differences in the expression of the VDR and the vitamin D activating enzyme CYP27B1 (15). Interestingly, observations from an adipose-specific Vdr knockout mouse model showed that adipocyte VDR signaling may alter body weight and fat mass in female but not male mice (16). Another sex difference in vitamin D metabolism is the high expression of 25-hydroxylase in testes compared to the ovaries (11); however, it is doubtful whether testicular conversion of cholecalciferol to 25(OH)D is contributing to systemic serum levels of 25(OH)D in men (33). Finally, women experience dynamic changes in the calciotropic hormones and minerals during pregnancy and lactation, which supports a sex difference in vitamin D metabolism (34).

At baseline, we found that women had a significantly higher serum HDL compared with men, which is in line with previous studies (35). One mechanism for this may be the sex-related difference in adipose tissue distribution since the circulating serum HDL concentration is directly influenced by adipose tissue (36). Additionally, women had higher serum adiponectin and leptin compared with men, which supports a sex difference in the regulation and release of adipokines from adipose tissue. The relationship between leptin and adiponectin has been proposed as a biomarker of adipose tissue dysfunction and the metabolic syndrome (37-39). At baseline, we found women had a significantly higher leptin/adiponectin ratio compared with men, which partially may be caused by differences in sex hormones (40).

The main function of PTH is to regulate calcium levels in the blood, and the hormone is released in response to a low serum calcium concentration. PTH is one of the strongest regulators of the vitamin D-activating enzyme CYP27B1 (8). We found the low-calorie diet-induced weight loss caused a decrease in serum PTH in both women and men. Despite women had a higher serum 25(OH)D and alb.corr. calcium compared to men at baseline, there was no difference in serum PTH between women and men. A sex difference in serum PTH has previously been noted (41).

The efficacy of GLP-1 receptor agonists on weight loss varies between individuals (42). Predictive markers for weight loss have been investigated with varying results (42-44). Obesity is strongly associated with low serum 25(OH)D, though vitamin D supplementation does not affect weight loss (9).

Vitamin D affects many different signaling pathways in adipose tissue such as adipogenesis, apoptosis, oxidative stress, inflammation, and lipid metabolism (12, 13). These processes are disturbed by vitamin D deficiency, indicating vitamin D may play a role in adipose tissue dysfunction; however, experimental and human studies have shown conflicting results (12, 13). Since dysfunctional adipose tissue is linked with the development of obesity-associated comorbidities, a distinction between dysfunctional and healthy adipose tissue may be of interest (45). Healthy adipose tissue is characterized by adipocyte hyperplasia, angiogenesis, and mitochondrial biogenesis in contrast to dysfunctional adipose tissue, which is characterized by adipocyte hypertrophy, defective angiogenesis, and mitochondrial derangement (45). Interestingly, local vitamin D metabolism in adipose tissue may differ between lean women and women with obesity and between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). Lean women have a higher expression of CYP27B1 and VDR in SAT compared with VAT and a lower expression of VDR in VAT compared with women with obesity (46). Moreover, in women, cholecalciferol has a higher affinity for storage in VAT compared with SAT (47), which may lead to a lower level of circulating 25(OH)D in women with a higher proportion of VAT indicative of a metabolically unhealthy adipose tissue distribution. Interestingly, fasting-induced weight loss in mice mobilized fat stores preferentially from VAT, leading to a greater proportional loss of fat mass in VAT compared to SAT (48, 49). Likewise, studies of weight loss in humans have shown that a higher proportion of fat mass is lost from VAT compared with SAT, though the total loss of fat mass is higher in SAT (50). These studies could indicate that dysfunctional adipose tissue is more dynamic than healthy adipose tissue and more sensitive to a negative calorie balance.

In our study, women experiencing a further weight loss at week 52 compared with week 0 had a higher serum leptin/adiponectin ratio and a lower serum HDL and, although not significant, tended to have a higher percentage of android fat mass at baseline compared with women who regained weight, indicating that women experiencing a further weight loss had a higher proportion of dysfunctional adipose tissue at baseline. Moreover, women experiencing a further weight loss at week 52 had a 23% lower serum 25(OH)D at baseline compared with women who regained weight, and we hypothesize that low serum 25(OH)D is a marker of dysfunctional adipose tissue in women with obesity.

The study is a secondary analysis and should be viewed as explorative, which is a limitation of the study. We recommend future studies specifically designed to investigate low vitamin D as a marker of dysfunctional adipose tissue in women and secondary as a predictive marker of persistent weight loss.

In conclusion, we show that a low-calorie diet-induced weight loss improved vitamin D status as serum 25(OH)D increased and serum PTH decreased in both women and men with obesity. Women experiencing a further weight loss after 1 year had an additional improvement in vitamin D status compared with women who regained weight, but this was not found in men, indicating a potential sex difference in vitamin D homeostasis. Finally, we found that low serum 25(OH)D in women may be a marker of dysfunctional adipose tissue and may predict successful weight loss maintenance.

Abbreviations

25(OH)D

25-hydroxyvitamin D

alb.corr. calcium

albumin-corrected calcium

BMI

body mass index

CYP24A1

24-hydroxylase

CYP27B1

1-alpha-hydroxylase

CYP2R1

25-hydroxylase

GLP-1

glucagon-like peptide-1

HOMA-IR

Homeostatic Model Assessment of Insulin Resistance

SAT

subcutaneous adipose tissue

VAT

visceral adipose tissue

VDR

vitamin D receptor

Contributor Information

Rune Holt, Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, Copenhagen University Hospital—Herlev and Gentofte, 2730 Herlev, Denmark; Group of Skeletal, Mineral and Gonadal Endocrinology, Department of Growth and Reproduction, Copenhagen University Hospital—Rigshospitalet, 2100 Copenhagen, Denmark.

Joachim Holt, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

Mads Joon Jorsal, Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, Copenhagen University Hospital—Herlev and Gentofte, 2730 Herlev, Denmark.

Rasmus Michael Sandsdal, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

Simon B K Jensen, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

Sarah Byberg, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

Christian Rimer Juhl, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

Julie Rehné Lundgren, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

Charlotte Janus, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

Bente Merete Stallknecht, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

Jens Juul Holst, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, 2200 Copenhagen, Denmark.

Anders Juul, Department of Growth and Reproduction, Copenhagen University Hospital—Rigshospitalet, 2100 Copenhagen, Denmark; International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital—Rigshospitalet, 2100 Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, 2100 Copenhagen, Denmark.

Sten Madsbad, Department of Endocrinology, Copenhagen University Hospital—Hvidovre, 2650 Hvidovre, Denmark.

Martin Blomberg Jensen, Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, Copenhagen University Hospital—Herlev and Gentofte, 2730 Herlev, Denmark; Department of Clinical Medicine, University of Copenhagen, 2100 Copenhagen, Denmark.

Signe Sørensen Torekov, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

Funding

This study was supported by an Excellence grant (NNF16OC0019968) from the Novo Nordisk Foundation, a grant from the Novo Nordisk Foundation Center for Basic Metabolic Research, a grant (NNF15CC0018486) from the Novo Nordisk Foundation Tripartite Immunometabolism Consortium, by Helsefonden, a grant from the Faculty of Health and Medical Sciences, University of Copenhagen, and a grant from the Danish Diabetes Academy, a PhD scholarship from the Danish Diabetes and Endocrine Academy funded by the Novo Nordisk Foundation (NNF22SA0079901), and the Department of Biomedical Sciences, University of Copenhagen. Novo Nordisk A/S supplied liraglutide and placebo pens and Cambridge Weight Plan provided meal replacements for the low-calorie diet. Funding partners had no influence on trial design, execution, data analysis, interpretation of the results, or communication of the results.

Author Contributions

S.S.T., J.R.L., C.J., B.M.S., J.J.H., and S.M. designed the study. S.B.K.J., R.M.S., C.R.J., J.R.L., and C.J. conducted the study. R.H. and J.H. analyzed the data. R.H. performed the statistical analyses. R.H., J.H., M.J.J., M.B.J., and S.S.T. wrote the first draft of the manuscript. All authors critically revised the manuscript and approved submission of the final version.

Disclosures

The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: R.M.S.: Family member holds Novo Nordisk stocks. S.B.: Received financial support for participation in a conference from Novo Nordisk. J.J.H.: Advisory board of Novo Nordisk A/S. S.M. (last 5 years): Advisory boards of AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Sanofi, Bayer; lecture fees from AstraZeneca; Novo Nordisk; research grant recipient, Novo Nordisk, Boehringer Ingelheim; support for attending meetings and/or travel from Novo Nordisk, Boehringer-Ingelheim. S.S.T.: research grants, lecture fee, advisory board meeting Novo Nordisk, lecture fee Merck. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data Availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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