Leptin, a hormone that regulates fat, also regulates bone formation
Osteoporosis is more prevalent in thin individuals than obese ones. The incidence of osteoporosis is also increased as a result of gonadal failure (e.g., with menopause). Leptin is a hormone that has been implicated in all three processes: regulation of bone mass, body weight and reproduction. Leptin deficient mice are obese, have high bone mass and are hypogonadal. Infusion of leptin into the third intracranial ventricle in mice causes weight loss and loss of bone mass. In previous work, Takeda et al have shown that leptin inhibits bone formation rather than promoting bone degradation.
Methods: Taked et al (Cell 111:305-317, 2002) explored the mechanism of leptin on bone formation. This is a lengthy study in which the investigators used a variety of in vitro assays and mouse models to try to dissect and differentiate the mechanisms of leptins effect on weight versus bone formation. The results (but not the detailed methods) will be summarized here.
Results: Both effects of leptin – the antiosteogenic effect and the anorexigenic (weight loss) effect – were confirmed to be mediated centrally through the hypothalamus. However, in contrast to the anorexigenic function of leptin, the peripheral mediators of its antiosteogenic function appeared to be mediated neuronally. Neuropeptides that mediate leptin anorexigenic function did not affect bone formation. Leptin deficiency resulted in low sympathetic tone. Genetic or pharmacological ablation of adrenergic sympathetic signaling led to leptin-resistant high bone mass. Beta-adrenergic receptors were demonstrated on osteoblasts and were shown to regulate the proliferation of these cells. Administration of a beta-adrenergic agonist decreased bone mass in leptin-deficient and wild-type mice, while a beta-adrenergic antagonist (propranol) was demonstrated to increase bone mass in both wild-type and ovariectomized mice. None of these manipulations affected body weight.
Conclusion: This study demonstrates leptin-dependent bone formation is mediated neuronally through the sympathetic nervous system. These findings have potential therapeutic implications for osteoporosis.
Editorial Comments: This is a remarkable study. These findings confirm that leptin has a negative regulatory effect on bone formation and this effect occurs independently (albeit concurrently) of its effect on weight. [Leptin suppresses bone formation and promotes weight loss through different pathways.] The finding that its antiosteogenic effect is mediated through the sympathetic nervous system has far-reaching clinical implications if it proves to be true for humans as well. Beta-blockers are used extremely commonly for management of high blood pressure and congestive heart failure. That these agents could also promote new bone formation introduces an entire new therapeutic area of investigation for the management of osteoporosis. It would be a very simple thing to confirm in man: does administration of a beta-blocker for 6-12 months enhance bone synthesis, as measured by bone synthesis biomarkers and by DEXA scan, compared to placebo-treated patients? One would guess that such a study is already in progress.
