Sci. Aging Knowl. Environ., 23 February 2005
Vol. 2005, Issue 8, p. nf16
[DOI: 10.1126/sageke.2005.8.nf16]


The Two Faces of Leptin

Fat-fighting hormone can strengthen, as well as weaken, the skeleton

Mitch Leslie

The hormone leptin not only trims fat but also thins the skeleton. However, a new study reveals that the hormone can sometimes bolster bones. The findings might help researchers create drugs to stall bone weakening after menopause.

The skeleton continually undergoes renovations. Cells called osteoclasts tear down bone, and cells called osteoblasts rebuild it. The balance between these processes dictates bone's density and strength. Molecular geneticist Gerard Karsenty of the Baylor College of Medicine in Houston, Texas, and colleagues showed 5 years ago that leptin, a hormone that keeps animals lean, also thins their skeletons. The researchers later demonstrated that leptin hinders bone formation by enlisting the sympathetic nervous system, which consists of nerves that control involuntary body processes such as heartbeat by releasing adrenaline and related messengers (see "The Plot Thickens on Thin Bones"). Karsenty and colleagues wondered whether the sympathetic nervous system also governs bone breakdown.

The researchers studied mice that lack the adrenaline receptor. Compared to normal animals, the altered rodents had extra-heavy skeletons and sported fewer osteoclasts. Next, the researchers prodded juvenile bone cells to develop into osteoclasts. Cells from the genetically altered rodents still matured, suggesting that their low numbers weren't due to a flaw in the osteoclasts. In bone, osteoblasts encourage osteoclast precursors to specialize. The team found that normal osteoblasts nudged more osteoclast progenitors to grow up than did osteoblasts from receptor-missing rodents. Together, these experiments suggest that the sympathetic nervous system provokes bone breakdown by stimulating osteoblasts to trigger osteoclast maturation.

Bone deterioration can accelerate after menopause, when estrogen quantities dwindle. To investigate how the sympathetic nervous system influences this cause of osteoporosis, the researchers removed the ovaries from mice deficient in the adrenaline receptor. The animals' skeletons didn't thin, indicating that adrenaline signals are necessary for postmenopausal bone loss. But the finding apparently clashes with other results. Rodents without leptin are sterile and have little sympathetic signaling--but their bone breakdown rate is higher than in adrenaline-insensitive mice. Leptin, the researchers reasoned, must rouse a molecule that counters its bone-thinning signal; one candidate was a protein called CART, which leptin activates but which doesn't alter metabolism. Mice lacking CART suffered more bone loss after a dose of leptin than did control rodents. Taken together, the findings suggest that leptin thins the skeleton by sparking the sympathetic nervous system and stimulating bone breakdown, but it also strengthens bone by activating CART. The results also indicate that a drug that could interdict sympathetic communication in the bones would prevent osteoporosis, says Karsenty.

The discovery of leptin's dual role "is exciting and provocative," says endocrinologist Stavros Manolagas of the University of Arkansas for Medical Sciences in Little Rock. "They are putting both arms of the [bone] remodeling process under the control of the sympathetic nervous system and leptin." The hormone seems to sense and fine-tune bone mass, Karsenty says, but how it determines where to set the balance between formation and destruction isn't clear. Further work might reveal how to adjust the hormone to keep older bones from losing weight.

February 23, 2005
  1. F. Elefteriou et al., Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature, 20 February 2005 [e-pub ahead of print]. doi:10.1038/nature03398
Citation: M. Leslie, The Two Faces of Leptin. Sci. Aging Knowl. Environ. 2005 (8), nf16 (2005).

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