1,25-Dihydroxyvitamin D3/vitamin D receptor suppresses brown adipocyte differentiation and mitochondrial respiration

Ricciardi, Carolyn J.; Bae, Ji‐Young; Esposito, Débora; Komarnytsky, Slavko; Hu, Pan; Chen, Jiangang; Zhao, Ling

doi:10.1007/s00394-014-0778-9

Cited by 61 publications

(54 citation statements)

References 36 publications

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“…Similar results, i.e. inhibited differentiation under 1,25(OH) 2 D, have also been reported in brown adipocytes (64) . However, these data have been recently challenged in human adipocytes where 1,25(OH) 2 D enhanced adipocyte differentiation and lipid accumulation (45) .…”

Section: Regulation Of Adipogenesissupporting

confidence: 88%

Vitamin D modulates adipose tissue biology: possible consequences for obesity?

et al. 2015

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Cross-sectional studies depict an inverse relationship between vitamin D (VD) status reflected by plasma 25-hydroxy-vitamin D and obesity. Furthermore, recent studies in vitro and in animal models tend to demonstrate an impact of VD and VD receptor on adipose tissue and adipocyte biology, pointing to at least a part-causal role of VD insufficiency in obesity and associated physiopathological disorders such as adipose tissue inflammation and subsequent insulin resistance. However, clinical and genetic studies are far less convincing, with highly contrasted results ruling out solid conclusions for the moment. Nevertheless, prospective studies provide interesting data supporting the hypothesis of a preventive role of VD in onset of obesity. The aim of this review is to summarise the available data on relationships between VD, adipose tissue/adipocyte physiology, and obesity in order to reveal the next key points that need to be addressed before we can gain deeper insight into the controversial VD-obesity relationship.Adipose tissue: Vitamin D: Obesity: Inflammation: Adipocytes: Nutrients: Nutrition Vitamin D: a brief overview Vitamin D (VD; calciferol) is a hormone mainly described for its role as a regulator of phosphate and calcium homeostasis (1) . It can be obtained through animal (VD 3 , cholecalciferol) or plant (VD 2 , ergocalciferol) food sources. Only a few foodstuffs contain significant amounts of VD, the main sources being fish liver oils, fatty fish (sardines, herring and mackerel) and egg yolk (2,3) , but small quantities are also found in fortified milk, orange juice, bread and cereals. Alternatively, VD 3 is produced endogenously in the skin after UVB irradiation from the precursor 7-dehydrocholesterol to give pre-VD 3 , which is further isomerised to VD 3 before being released into the circulation (4) . Classical estimates have assigned a majority (70-90 %) of VD supply to dermal synthesis, but a recent paper revised this figure down to just 10-25 % of VD supply (5) and posited that dietary intake of 25-hydroxy-vitamin D (25(OH)D) is a significant contributor to total VD input.Adipose tissue is a major storage site for vitamin D Despite limited data, it is widely accepted that adipose tissue is a reservoir for VD in human subjects and rats (6)(7)(8)(9)(10) . Interestingly, visceral fat was found to contain 20 % more VD than subcutaneous fat (11) . Heaney et al. (12) calculated that 65 % of total VD in the body is in the form of D 3 , for which adipose tissue and skeletal muscle appear to be the main body stores (accounting for 73 and 16 %, respectively).

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Section: Regulation Of Adipogenesissupporting

confidence: 88%

Vitamin D modulates adipose tissue biology: possible consequences for obesity?

et al. 2015

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“…Consistent with comparable serum leptin in CVF and CN1 mice on the high fat diet, Leptin gene expression was equivalent in adipose tissue. In contrast, the brown fat identity gene Ucp1 which is repressed by Vdr (25, 26) was significantly elevated in white adipose tissue of CVF mice. The dramatic increase in Ucp1 (>40 fold higher than that of CN1 mice) is consistent with previous observations in white adipose tissue of global VDRKO mice (2).…”

Section: Resultsmentioning

confidence: 84%

Adipose-specific Vdr deletion alters body fat and enhances mammary epithelial density

Matthews

D’Angelo

Drelich

et al. 2016

The Journal of Steroid Biochemistry and Molecular Biology

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Vitamin D status has been associated with obesity, metabolic syndrome and several cancers including colon and breast. Since adipocytes express VDR and obesity is a known risk factor for cancer, vitamin D actions in adipose tissue may contribute to its cancer protective effects. In the mammary gland, signaling from adipocytes to epithelial cells is necessary for breast cancer initiation, but the impact of vitamin D on this cross-talk is unclear. To examine the role of VDR in adipose tissue, particularly in the context of the mammary gland, we crossed Vdr-flox mice with Fabp4-cre mice to generate mice with adipose-specific Vdr deletion (termed CVF mice). CVF mice and Fabp4-cre control mice (termed CN1 mice) were reared on high calcium “rescue” diets (for comparison to global VDRKO mice) or on high fat diets (to stimulate adiposity). Vdr expression was significantly reduced in adipose tissue of CVF mice compared to CN1 mice. In contrast to global VDRKO mice (which exhibit adipose atrophy), female CVF mice exhibited higher growth rates and increased visceral fat pad weight compared to control mice. Expression of Ucp1 and Pparg were elevated in white adipose tissue of CVF mice supporting these genes as Vdr targets in mature adipocytes. Adipose-specific Vdr deletion did not impair glucose tolerance or alter the weight of brown adipose tissue, liver, pancreas or bone in response to high fat feeding. In contrast to the effect of adipose-specific Vdr deletion on visceral fat pads, the weight of the subcutaneous (mammary) fat pad was not increased in high fat fed CVF female mice compared to control mice. Quantitative analysis of mammary ductal development on whole mounts and H&E stained sections indicated that adipose-deletion of Vdr significantly enhanced mammary epithelial density and branching. Collectively, these data support the hypothesis that Vdr in mature adipocytes alters the metabolic response to high fat diets and exerts anti-proliferative effects on the mammary epithelium.

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“…25(OH)D 3 and 1,25(OH) 2 D 3 repletion attenuated perturbations of UCPs and ATP contents in adipose tissues and muscle in Ctns À/À mice. 1,25(OH) 2 D 3 suppresses UCPs expression in primary brown adipocyte and suppresses differentiation and mitochondrial respiration of brown adipocyte 39, 40 1,25(OH) 2 D 3 /VDR by binding to the promoter region of the UCP3 gene and modulating UCP3 gene transcription and subsequent energy metabolism in muscle. 41 Figure 4 Vitamin D repletion modulates expression of key molecules implicated in adipose tissue browning in Ctns À/À mice.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D repletion ameliorates adipose tissue browning and muscle wasting in infantile nephropathic cystinosis‐associated cachexia

Cheung

Sheng

Wang

et al. 2019

J cachexia sarcopenia muscle

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Background Ctns−/− mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Ctns−/− mice are 25(OH)D3 and 1,25(OH)2D3 insufficient. We investigated whether vitamin D repletion could ameliorate adipose tissue browning and muscle wasting in Ctns−/− mice. Methods Twelve‐month‐old Ctns−/− mice and wild‐type controls were treated with 25(OH)D3 and 1,25(OH)2D3 (75 μg/kg/day and 60 ng/kg/day, respectively) or an ethylene glycol vehicle for 6 weeks. Serum chemistry and parameters of energy homeostasis were measured. We quantitated total fat mass and studied expression of molecules regulating adipose tissue browning, energy metabolism, and inflammation. We measured lean mass content, skeletal muscle fibre size, in vivo muscle function (grip strength and rotarod activity), and expression of molecules regulating muscle metabolism. We also analysed the transcriptome of skeletal muscle in Ctns−/− mice using RNAseq. Results Supplementation of 25(OH)D3 and 1,25(OH)2D3 normalized serum concentration of 25(OH)D3 and 1,25(OH)2D3 in Ctns−/− mice, respectively. Repletion of vitamin D partially or fully normalized food intake, weight gain, gain of fat, and lean mass, improved energy homeostasis, and attenuated perturbations of uncoupling proteins and adenosine triphosphate content in adipose tissue and muscle in Ctns−/− mice. Vitamin D repletion attenuated elevated expression of beige adipose cell biomarkers (UCP‐1, CD137, Tmem26, and Tbx1) as well as aberrant expression of molecules implicated in adipose tissue browning (Cox2, Pgf2α, and NF‐κB pathway) in inguinal white adipose tissue in Ctns−/− mice. Vitamin D repletion normalized skeletal muscle fibre size and improved in vivo muscle function in Ctns−/− mice. This was accompanied by correcting the increased muscle catabolic signalling (increased protein contents of IL‐1β, IL‐6, and TNF‐α as well as an increased gene expression of Murf‐2, atrogin‐1, and myostatin) and promoting the decreased muscle regeneration and myogenesis process (decreased gene expression of Igf1, Pax7, and MyoD) in skeletal muscles of Ctns−/− mice. Muscle RNAseq analysis revealed aberrant gene expression profiles associated with reduced muscle and neuron regeneration, increased energy metabolism, and fibrosis in Ctns−/− mice. Importantly, repletion of 25(OH)D3 and 1,25(OH)2D3 normalized the top 20 differentially expressed genes in Ctns−/− mice. Conclusions We report the novel findings that correction of 25(OH)D3 and 1,25(OH)2D3 insufficiency reverses cachexia and may improve quality of life by restoring muscle function in an animal model of infantile nephropathic cystinosis. Mechanistically, vitamin D repletion attenuates adipose tissue browning and muscle wasting in Ctns−/− mice via multiple cellular and molecular mechanisms.

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1,25-Dihydroxyvitamin D3/vitamin D receptor suppresses brown adipocyte differentiation and mitochondrial respiration

Abstract: Our results demonstrate the suppressive effects of 1,25(OH)2D3/VDR signaling on brown adipocyte differentiation and mitochondrial respiration. The role of 1,25(OH)2D3/VDR system in regulating BAT development and function in obesity warrant further investigation.

Cited by 61 publications

References 36 publications

Vitamin D modulates adipose tissue biology: possible consequences for obesity?

Vitamin D modulates adipose tissue biology: possible consequences for obesity?

Adipose-specific Vdr deletion alters body fat and enhances mammary epithelial density

Vitamin D repletion ameliorates adipose tissue browning and muscle wasting in infantile nephropathic cystinosis‐associated cachexia

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