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Obesity and Type 2 Diabetes May Be Bred in the Bone


NEW YORK -- Bone-generating osteoblasts secrete a protein that appears to regulate insulin function and glucose metabolism, revealing an endocrine role for the skeleton, researchers here said.

NEW YORK, Aug. 9 -- The skeleton may play a role in regulating glucose metabolism and fat storage, a discovery that would support those who blame their girth on their bone structure, investigators here reported.

In a study of mice, bone-generating osteoblasts secreted osteocalcin, a hormone-like protein that protects against obesity and glucose intolerance by increasing proliferation of pancreatic beta cells and insulin secretion, reported Gerard Karsenty, M.D., Ph.D., of Columbia University, and colleagues. Simultaneously it boosted insulin sensitivity.

"Our results expand the spectrum of functions of skeleton, add further credence to the concept that bone and energy metabolisms regulate each other, and also suggest that the pathogenesis of some degenerative diseases of energy metabolism may be more complex than anticipated," the team wrote in the Aug. 10 issue of Cell.

The finding suggested that the skeleton has a previously undiscovered function, and that manipulating osetocalcin levels might be an effective strategy for treating type 2 diabetes.

"The discovery that our bones are responsible for regulating blood sugar in ways that were not known before completely changes our understanding of the function of the skeleton and uncovers a crucial aspect of energy metabolism," Dr. Karsenty said.

The investigators were prompted to explore the relationship between skeletal biology and endocrine regulation by the observation that in mammals' obesity is protective against osteoporosis.

They had previously shown that leptin, a hormone derived from adipocytes, regulates bone remodeling by acting on osteoblasts through two distinct neural pathways.

"Regardless of the molecular complexity of this neuroendocrine regulation, if indeed bone cells determine the level of activity of hormone-producing cells, then osteoblasts should affect energy metabolism," they reasoned.

To test this theory they looked at osteoblasts for the presence of genes that encode for signaling molecules and affect energy metabolism. One such molecule is osteocalcin, known to be secreted only by osteoblasts and by Sertoli cells in the testes.

The authors had previously seen that mice bred to be deficient in osteocalcin had abnormal amounts of visceral fat.

"This was the initial evidence suggesting that skeleton may regulate energy metabolism," they wrote.

In the current study, they generated mutant mouse strains that were lacking genes encoding for signaling molecules that were expressed only -- or preferentially -- in osteoblasts.

They found that mice with an inactivated osteoblast gene called Esp, which encodes for a receptor-like protein tyrosine phophatase called OST-PTP were hypoglycemic and were protected from type 2 diabetes by having increased beta-cell proliferation, plus an increase in both insulin secretion and insulin sensitivity.

When the investigators looked for the specific proteins secreted by osteoblasts that might govern the the metabolic effects seen in the Esp-deficient mice, they identified osteocalcin as the most likely candidate. The authors affirmed the metabolic importance of the protein by observing that deleting one allele of the gene encoding for osteocalcin reversed the beta-cell proliferation and insulin secretion and sensitivity effects they had seen.

Furthermore, deletion of both alleles of the osteocalcin gene resulted in mice that were both glucose intolerant and fat.

"To our knowledge this study provides the first in vivo evidence that skeleton exerts an endocrine regulation of energy metabolism and thereby may contribute to the onset and severity of metabolic disorders," they wrote.

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