Leptin and Bone Metabolism

Leptin has been proposed as mediating the protective effects of obesity on the skeleton similarly to traditional factors, such as mechanical loading and increased levels of estrogens and insulin [117]. Leptin shows both a peripheral and positive action on bone as well as a central and negative control of bone metabolism [118-122]. Considering the conflicting and sometimes contradictory data published in the literature, it remains difficult to draw a clear picture harmonizing these dual eVects of leptin on bone metabolism.

9.1. Peripheral Effect of Leptin on Bone Metabolism

The expression of both short and long forms of leptin receptor was first recognized in human marrow stromal cells [123] and more recently in primary cultures of normal human osteoblasts [124]. In different cell models, leptin stimulates human osteoblastic cell diVerentiation [123, 125], bone matrix mineralization [123-125], and collagen synthesis [125] with protective effects against osteoblastic apoptosis [125]. Leptin could be considered one of the factors that could shift the differentiation of stromal cells from an adipocytic to an osteoblastic pathway. This would occur through activation of the mitogen-activated protein kinase (MAPK) cascade. MAPK is involved both in osteoblastic diVerentiation as well in the phosphorylation of peroxi-some proliferator-activated receptor 7 (PPAR7), a mechanism shown to inhibit adipogenesis [121].

In addition to its positive eVect on the osteoblastic lineage, leptin may modulate osteoclast diVerentation and function. In experimental studies [126, 127], leptin inhibited osteoclast generation via reduction in expression of the soluble receptor activator of nuclear factor-^B (sRANK) as well as through increased secretion of osteoprotegerin (OPG), its decoy receptor, by stromal cells.

Several in vivo studies, conducted in diVerent animal models confirm and support the findings obtained from in vitro experiments. Steppan et al. [128] showed that leptin administration to leptin-deficient (ob/ob) mice led to a significant increase in bone mineral content and density. Similarly, leptin administration to ovariectomized rats prevented bone loss induced by estrogen deficiency or disuse [127]. Both in vitro and in vivo studies appear to support the hypothesis that leptin directly and positively aVects bone metabolism by modulating both osteoblast and osteoclast generation and function.

9.2. Central Effect of Leptin on Bone Metabolism

In contrast to the evidence for a positive peripheral role of leptin on bone metabolism, ob/ob, and leptin receptor-deficient (db/db) mice presented a phenotype characterized by increased bone mass with an increased rate of bone formation despite hypogonadism and hypercortisolism [129]. In this study, there was no expression of leptin receptors on osteoblasts, whereas the intracerebroventricular infusion of leptin decreased bone formation rate in ob/ob mice as well as in wild-type animals [129]. Mice knock-in of LacZ in the leptin locus with increased circulating leptin level had a dramatically reduced bone mass [130]. In this experimental model, leptin synthesis was not detected in the CNS. As such, circulating leptin must therefore account for the observed antiosteogenic eVect with similar amounts of leptin needed to aVect both body weight and bone mass [130].

Mice Leptin Level
  1. 3. Central and peripheral leptin control of bone metabolism. OPG = osteoprotegerin; RANK = receptor activator of NF-reB; RANKL = receptor activator of NF-reB ligand; VMN = ventromedial hypothalamic nucleus; ARC = arcuate nucleus; NPY = neuropeptide Y; POMC = pro-opiomelanocortin; CART = cocaine amphetamine-regulated transcript; SNS = sympathetic nervous system. Peripherically circulating leptin secreted by fat tissue or locally produced by osteoblasts and/or bone marrow adipocytes, inhibits osteoclast precursors
  2. 3. Central and peripheral leptin control of bone metabolism. OPG = osteoprotegerin; RANK = receptor activator of NF-reB; RANKL = receptor activator of NF-reB ligand; VMN = ventromedial hypothalamic nucleus; ARC = arcuate nucleus; NPY = neuropeptide Y; POMC = pro-opiomelanocortin; CART = cocaine amphetamine-regulated transcript; SNS = sympathetic nervous system. Peripherically circulating leptin secreted by fat tissue or locally produced by osteoblasts and/or bone marrow adipocytes, inhibits osteoclast precursors

It has also been shown that leptin action on bone may be dependent on activation of different hypothalamic nervous circuits than those mediating anorexigenic action of leptin [131]. In fact, experiments of selective destruction of hypothalamic nuclei suggest that neurons of the ventromedial nucleus may be implicated in leptin antiosteogenic function [131]. However, there is also evidence that peptides produced by the arcuate nucleus, under lep-tin control, could play a role in regulating bone metabolism [118, 119]. NPY decreases bone mass when administered centrally [129], whereas mice knockout for NPY receptors have increased bone formation [132]. Similarly a-Melanocyte stimulating hormone has been shown to have stimulatory effects on osteoblast function and osteoclasteogenesis [133]. When systemi-cally administered to mice, this hormone decreased bone volume via increased bone turnover [133].

Leptin activates the sympathetic nervous system with a stimulation of ,32-adrenergic receptors on the surface of the osteoblasts and a final reduction in bone formation [131]. In fact, mice lacking a key enzyme in the production of norepinephrine and epinephrine have a higher bone mass than wild-type animals [131]. Intracerebral infusion of leptin resulted in decreased fat mass but not bone mass. This finding showed that osteogenic action of leptin, not its anorexigenic effect, is dependent on the sympathetic nervous system [131].

In conclusion, the findings from in vitro and in vivo studies appear to support the existence of two conflicting pathways in leptin regulation of bone mass (Fig. 3): a central negative mechanism opposed to a peripheral and positive control of bone metabolism.

An explanation for the existence of these conflicting effects of leptin on bone has been recently proposed by Khosla [120]. Leptin level falls in response to starvation. This phenomenon triggers a hormonal compensative response necessary for survival but devastating to the skeleton. To overcome this effect, a central mechanism may have naturally developed to increase bone formation despite low leptin level [120]. Conversely, under conditions of rising fat stores, leptin levels increase. A situation of central inhibition of bone formation may thus occur if the positive peripheral effects of leptin did diVerentiation and proliferation through an increased production of osteoprotegerin from pre-osteoblasts as well as through a reduction of the expression of RANKL on osteoblasts surface; osteoprotegerin prevent the interaction between RANK receptors on osteoclast progenitors and RANKL on the surface of osteoblastic cells. Leptin through an increased production of IGF-1 and TGF-,3 from osteoblasts, stimulates the proliferation of osteoprogenitor cells, bone matrix mineralization and prevent osteoblasts apoptosis. Centrally (dashed lines) leptin activates neurons in the hypothalamus, in particular ARC and VMN through still not well-characterized neuropeptides; leptin determines an activation of the sympathetic nervous system with an increase in norepinephrine that stimulates receptors on osteoblasts surface with a reduction in bone formation.

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