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. 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 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. Leptin receptors are also found outside the hypothalamus in insulin-producing b cells, bone marrow stromal cells, osteoblasts and chondrocytes, and kidney cells. 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 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 [ΒΌ 25(OH)D 1a-hydroxylase] that could be corrected by intraperitoneal leptin injections. The same group 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 1ahydroxylase activity. clearly demonstrating the indirect effects of leptin.