The white adipose tissue connection with calcium and bone homeostasis

Abstract

T he idea of fat cells and tissue being the passive storage site of excess energy has long been gone. Not surprisingly, fat cells (white adipose tissue) were first recognized as being the source of hormones controlling energy homeostasis because they secrete more leptin with increasing fat stores. (1) Leptin then crosses the blood-brain barrier to activate its receptor in the hypothalamic regions, thereby starting a complex feedback on energy intake and expenditure but also regulating other systems such as sexual maturation and reproduction (2) and bone homeostasis. (3) Indeed, a series of elegant studies of the Karsenty group clearly demonstrated that central activation of leptin signaling activates the sympathetic postganglionic neuronal system that ultimately decreases bone formation and increases bone resorption. (3,4) Leptin receptors are also found outside the hypothalamus in insulin-producing b cells, bone marrow stromal cells, osteoblasts and chondrocytes, and kidney cells. (5) This suggests a much wider spectrum of activities for this fat cell signal, not mediated by a central neuroendocrine system.A few years ago, Horiuchi's laboratory (6,7) described increased serum concentrations of 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], calcium, and phosphate in leptin-deficient (ob/ob) mice owing to increased renal expression of CYP27B1 [¼ 25(OH)D 1a-hydroxylase] that could be corrected by intraperitoneal leptin injections. The same group (8) now expands this observation by demonstrating that leptin stimulates the osteoblast (osteocyte?) production of fibroblast growth factor 23 (FGF-23), which is thereafter responsible for the downregulation of CYP27B1 and of the sodium-phosphate cotransporters (NaPT-II). The overproduction of 1,25(OH) 2 D 3 also was present in mice with leptin receptor deficiency (db/db mice) but could not, in contrast to the ob/ob mice, be corrected by intraperitoneal leptin injection. FGF-23 therapy also corrected the overproduction of 1,25(OH) 2 D 3 in ob/ob mice (not reported for db/db mice). Addition of leptin to renal tubular cell cultures did not modify the local 1a-hydroxylase activity. (8) clearly demonstrating the indirect effects of leptin.What Are the Implications of These Observations?F irst, the new data further elucidate the complex regulation of the renal production of the vitamin D hormone. Indeed, it is now well established that calcium/calcium sensing receptordriven parathyroid hormone (PTH) secretion constitutes the major stimulus for renal 1a-hydroxylase and thus the production of systemic 1,25(OH) 2 D 3 while shutting down the expected renal activation of CYP24A1, the major degradation system for vitamin D metabolites. (9)(10)(11) The second systemic hormone, osteocytic FGF-23, is a negative regulator of renal 1a-hydroxylase activity, whereas both PTH and FGF-23 decrease the tubular reabsorption of phosphate by downregulation of NaPT-II. The PTH and FGF-23 hormones thus regulate vitamin D activation, as driven by calcium and phosphate, respectively (12)(13)(14) (Fig. 1...

Vitamin D Metabolism Revised: Fall of Dogmas

“…In these non‐renal tissues, a different region of the CYP27B1 enhancer region was regulated by inflammatory factors, consistent with different regulatory mechanisms in non‐renal tissues by the cytokines interferon‐γ and tumor necrosis factor‐α. Leptin may also (negatively) regulate CYP27B1 but probably mainly by its stimulatory effect on FGF23 production . These feedback loops provide very tight regulation of 1,25(OH) 2 D production by the PCT of the kidney, control that differs from that of CYP27B1 in other cell types including that of distal renal tubule cells where PTH has little effect …”

Bone Remodeling and Energy Metabolism: New Perspectives

“…Leptin crosses the blood-encephalic barrier to stimulate its receptor in the hypothalamus, thereby triggering complex actions related to energy modulation, pubertal onset and control of bone remodeling. Mice with congenital absence of leptin (ob/ob mice) or the leptin receptor (db/db mice) exhibit a complex phenotype, including obesity and high bone mass in the vertebrae (117,118). This occurs despite hypogonadism and hypercortisolism, conditions that would tend to lower bone mass in mice.…”

How to Define Optimal Vitamin D Status

“…That is usually the case when the vitamin D status is sufficient in view of the precursor/threshold status of 25(OH)D so that the kidney, the only tissue that under normal conditions produces 1,25(OH) 2 D for export to serum, can synthesize the optimal amount of hormone, based on other input stimuli such as PTH, FGF23, and calcitonin [21]. However, other studies demonstrate a clear positive correlation and such studies are usually indicative of a vitamin D insufficiency status as this indicates that the precursor, 25(OH)D, is limiting the renal hormone production.…”

“…VDR null mice as well as cyp27b1 null mice are leaner than controls and more resistant to diet-induced obesity by actions not completely understood. Whether this feedback loop is also operational in humans is yet unknown [21]. Also see Chapter 44 for a discussion of new concepts regarding vitamin D and adipose tissue.…”