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Vitamin D Deficiency and Energy Metabolism David R. Fraser Faculty of Veterinary Science, The University of Sydney, New South Wales 2006, Australia

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he discovery, more than 30 years ago, of the presence of the 1,25-dihydroxyvitamin [1,25(OH)2D] receptor protein [vitamin D receptor protein (VDR)] in cells, such as those in the pancreas (1), with no apparent function in calcium homeostasis, opened up several unexpected new lines of research. First, the identification of the VDR in a wide range of cell types (2) led to the recognition that vitamin D has pervasive endocrine roles on cell differentiation in many physiological systems. Second, this began to provide some rational basis, for explaining the many reports of epidemiological associations between low vitamin D status and a variety of common, and not so common, human diseases, which show no link to defects in calcium homeostasis (3). Third, the application of molecular biological techniques in vitro to different cell types expressing the VDR has demonstrated the true steroid hormone function of 1,25(OH)2D (4). Despite this large body of new knowledge, the integration of novel vitamin D functions in whole-body physiology is still not well understood. It is now thought that the supply of 1,25(OH)2D to act on the VDR in many cells comes mainly from paracrine or autocrine local synthesis, an interpretation of the widespread expression in different tissues of the 1␣-hydroxylase (CYP27B1). The classical renal production of 1,25(OH)2D and its regulation seem to be more related to the requirements for maintaining calcium homeostasis than to the panoply of other endocrine functions of vitamin D. Moreover, unlike the renal 1␣-hydroxylase, which is well regulated according to the needs for 1,25(OH)2D in calcium homeostasis and is relatively independent of the substrate supply of 25-hydroxyvitamin D [25(OH)D], the activities of the 1␣-hydroxylases in other tissues are largely determined by the concentration of 25(OH)D in the extracellular fluid. Hence, when vitamin D status falls,

the nonrenal regional production of 1,25(OH)2D also declines with a consequent reduction in its autocrine or paracrine functions (5). The assumption from this is that maintenance of good vitamin D status would be essential to avoid the development of disease as a consequence of inadequate local production of 1,25(OH)2D to maintain its many autocrine or paracrine roles. However, one of the truisms of vitamin D physiology is that in temperate regions of the world, the vitamin D status of humans and other animals rises in summer and declines in winter in response to seasonal variation in the intensity of solar UV light. How then are the paracrine/ autocrine functions of 1,25(OH)2D maintained during the weeks or months of seasonal low vitamin D status? Could it be that there has been some evolutionary adaptation to the seasonal change in vitamin D status that is reflected by seasonal changes in some paracrine/autocrine roles of 1,25(OH)2D? One of the tantalizing possible new roles for 1,25(OH)2D is as another hormone in the regulation of whole-body energy metabolism. The VDR has been identified in cells of the pancreas (1), adipose tissue (6), liver (7), and now the myocytes of skeletal muscle (8), all key organs in energy metabolism and nutritional energy balance. Vitamin D deficiency is often found in people with the insulin resistance of type 2 diabetes (9) as well as when there is defective insulin secretion (10). Now Liu et al (11) report in this issue that vitamin D deficiency minimizes hyperinsulinemia and lipid accumulation in the liver of mice fed a high-fat diet. In agreement with other studies, these authors also show that vitamin D deficiency itself does not lead to obesity, even though obesity in humans is often associated with low vitamin D status (12). However, the surprising findings of Liu et al were that the vitamin D-deficient mice dem-

ISSN Print 0013-7227 ISSN Online 1945-7170 Printed in U.S.A. Copyright © 2015 by the Endocrine Society Received April 1, 2015. Accepted April 15, 2015.

Abbreviations: 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)2D, 1,25-dihydroxyvitamin D; VDR, vitamin D receptor protein.

For article see page 2103

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onstrated an increased expression in white adipose tissue of key genes in the ␤-oxidation of fatty acids along with uncoupling of ATP formation. Here is experimental evidence to suggest that vitamin D deficiency, which is frequently found in human nonalcoholic fatty liver disease (13), may not be causative of the hepatic accumulation of fat. These results are compatible with another publication (14) that reports an increased energy expenditure in white adipose tissue cells in VDR knockout mice. Thus, here are situations in which low vitamin D status, or the absence of vitamin D function as in VDR knockout mice, both demonstrate what might be considered a beneficial effect of increasing energy release as heat from the oxidation of dietary fatty acids in adipose tissue rather than storing that energy as triacyl glycerol. Is this just evidence for a further mysterious role for 1,25(OH)2D in the complexities already discovered for vitamin D function in adipose tissue (15)? Or is it too fanciful to suggest that there might be some advantage for the maintenance of body temperature if there is increased oxidation of fatty acids with release of energy as heat when vitamin D status is low as in winter? In human obese subjects, the expression of the VDR gene in adipose tissue is increased (16). This implies that there would be an increased requirement for the VDR ligand, 1,25(OH)2D, and this would not be met if the circulating concentration of substrate 25(OH)D is low. There is evidence that some action of vitamin D diminishes the inflammatory response in adipose tissue in obesity (15, 17). The usual explanation for the observation that vitamin D status is lower in obese people compared with nonobese is that the large mass of adipose tissue traps some incoming vitamin D, thus diminishing the supply for 25(OH)D formation in the liver. However, could it be that the enhanced need for 1,25(OH)2D in adipose tissue in obesity is depleting circulating 25(OH)D at a faster rate than would be the case if there were less adipose tissue? If the findings of Liu et al (11) in mice are transferable to humans, how might they explain a role for changes in vitamin D status in the development of obesity? From their results it would seem that an increase in circulating 25(OH)D, leading to more local production of 1,25(OH)2D, would suppress fatty acid oxidation, thus giving a greater mass of adipose tissue. This would not fit with the observation that low vitamin D status is a characteristic of obesity in humans. Perhaps then the impact of vitamin D status on excessive storage of energy in adipose tissue lies elsewhere such as with the influence of 1,25(OH)2D on the secretion of insulin or even of PTH. There are several reports that increased dietary calcium

Endocrinology, June 2015, 156(6):1933–1935

intake leads to a decrease in adipose tissue mass (18). Also, mitochondria from liver or brown adipose tissue of obese mice demonstrate increased rates of calcium cycling across the mitochondrial membrane compared to lean mice (19). These observations suggest that the role of vitamin D in calcium homeostasis, as well as its many other endocrine roles, may all modify energy metabolism. Further research using the techniques of Liu et al might eventually reveal how variation in vitamin D status alters all the endocrine systems that affect the growth of adipose tissue. This could then give rise to practical strategies to help in the control or prevention of obesity.

Acknowledgments Address all correspondence and requests for reprints to: David R. Fraser, BVSc, PhD, Faculty of Veterinary Science, The University of Sydney, New South Wales 2006, Australia. E-mail: [email protected] Disclosure Summary: The author has nothing to declare.

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13. Eliades M, Spyrou E. Vitamin D: a new player in non-alcoholic fatty liver disease? World J Gastroenterol. 2015;21:1718 –1727. 14. Narvaez CJ, Matthews D, Broun E, Chan M, Welsh J. Lean phenotype and resistance to diet-induced obesity in vitamin D receptor knockout mice correlates with induction of uncoupling protein-1 in white adipose tissue. Endocrinology. 2009;150:651– 661. 15. Ding C, Gao D, Wilding J, Trayhurn P, Bing C. Vitamin D signalling in adipose tissue. Br J Nutr. 2012;108:1915–1923. 16. Clemente-Postigo M, Munoz-Garach A, Serrano M, et al. Serum 25-hydroxyvitamin D and adipose tissue vitamin D receptor gene

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