Role of leptin in bone growth: central player or peripheral supporter?

Maintenance or gain of bone mass is associated with hormone and/or heavy mechanical load, either due to obesity or physical activity [1]. Amongst the many hormones that might account for the link between energy and bone metabolism is leptin. In this respect, much attention has focused on the e¡ects of leptin as a central satiety agent, although in vitro studies provide evidence for direct e¡ects on speci¢c tissues and metabolic pathways. The debate related to central and/or peripheral regulation of bone metabolism by leptin has been ongoing during the last 2 years. The article by Lee and colleagues [2] in this issue further addresses this topic, and provides evidence that functional leptin receptors are expressed in rat osteoblasts. These results point towards a more direct role of leptin in bone growth. Since its discovery in 1994 [3], leptin has been acknowledged as an adipocyte-derived signaling molecule, which may limit food intake and increase energy expenditure via speci¢c receptors located in the central nervous system. However, the picture is becoming more complicated, and leptin is now looked upon as a multi-potent cytokine with both indirect central and direct peripheral e¡ects in di¡erent organs, tissues and cells. Circulating leptin in adult individuals is mainly secreted from adipose tissue [3,4], although leptin polypeptide and mRNA are detected in other tissues like muscle [5], gastric epithelium [6], bone [7], and in breast epithelial cells [8]. Leptin expression has also been found in arterial wall cells [9] and in normal pituitary and di¡erent types of pituitary adenomas [10]. In pregnant women, leptin is synthesized and secreted from placental trophoblasts into the maternal and fetal circulation [11]. Leptin binds to receptors in the hypothalamus [4] which leads to reduced appetite and increased energy expenditure. The leptin receptor (OB-R) exhibits considerable homology with the interleukin-6 (IL-6) receptor and belongs to the cytokine class I receptor family [12]. At least six forms of the leptin receptor have been found, of which the long signaltransducing form, OB-RL, presumably mediates most of leptin’s signaling events. It is also the isoform most abundantly expressed in the hypothalamus [12]. However, the leptin receptor is expressed in various areas of the central nervous system, and in many other organs and cell types [13]. The cytokine receptor superfamily is a rapidly growing family of receptors. An early and most likely pivotal event for all subspecies is the activation of one or more members of the Janus (or JAK) family of tyrosine kinases. The activated JAK kinases, which form a complex with the cytokine receptor subunits, induce autophosphorylation as well as phosphorylation of the receptor. These phosphorylated tyrosines form binding sites for various signaling molecules that are themselves thought to be phosphorylated by JAK kinases, including signal transducers and activators of transcription (STATs) [14], which regulate transcription by adapter proteins like SH2-containing protein tyrosine phosphatase [15] that recruit Grb2 complexes thereby initiating the mitogen-activated protein kinase (MAPK) pathway, and insulin receptor substrate (IRS) proteins that, through phosphate inositol pathway, are thought to regulate metabolic events in the cell [16].