Vitamin D deficiency and energy metabolism.

Abstract

The 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-