Don't be fooled by the rigid feel and appearance of a skeleton. The 206 bones in the human body not only support it but are in a constant state of flux, breaking down and rebuilding themselves as well as manufacturing blood cells in their marrow. But that is not all they do. A new study shows that the skeleton is also an endocrine organ involved in energy metabolism, and as such may play a role in weight gain and loss: Bones regulate glucose (blood sugar) by secreting osteocalcin, a hormone that enhances insulin activity and reduces obesity and type 2 diabetes in mice.

"It's exciting because of the therapeutic implications. There is a novel way of regulating glucose metabolism [that could lead to] a breakthrough in the treatment in type 2 diabetes," says Gerard Karsenty, chair of the genetics and development department at Columbia University Medical Center in New York City and lead author of the study published in the journal Cell.

Karsenty and his colleagues decided to probe further after finding last year that leptin, a hormone secreted by fat cells, regulates bone mass. If fat cells are talking to bone cells, they wondered, are the bone cells talking back?

"We wanted to test the hypothesis that bone cells, in turn, were regulating fat cells," Karsenty explains. So the team set out to identify which of the few genes that operate primarily in bone cells are linked to glucose metabolism. They "knocked out'' (inactivated) these genes in mice and discovered that the animals lacking a functional osteocalcin gene were fat and also glucose intolerant, both prediabetic conditions.

Further investigation revealed that osteocalcin signals fat cells to release adiponectin, a hormone that increases insulin sensitivity, confirming researchers' suspicions that bone cells communicate with fat cells. What's more, osteocalcin triggers the production of more pancreatic beta cells, the body's insulin factories, and increases their output, thus making more insulin available to the body.

"These properties are rather unusual," Karsenty says, noting that it is rare to find a hormone that simultaneously ups production and insulin sensitivity. Researchers are optimistic that one day osteocalcin may be used to treat type 2 diabetes by helping patients make and use insulin more effectively.

"So far, most of the drugs that we use [for type 2 diabetes] work on [only] one pathway at once," says Manu V. Chakravarthy, an endocrinologist and diabetes researcher at Washington University in St. Louis School of Medicine. "[Osteocalcin] is a promising candidate because it does both."

But can the results be duplicated in humans? "You can never be sure but it's fairly likely that it happens in humans, because the hormone is made in humans," Karsenty says, noting that people with type 2 diabetes generally also have low osteocalcin levels.

Type 2 diabetes—the variety of the disease associated with obesity and a sedentary lifestyle—accounts for up to 95 percent of U.S. cases and has nearly tripled over the past 25 years or so, according to the Centers for Disease Control and Prevention. It now afflicts some 21 million Americans, or 7 percent of the U.S. population.

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