Endocrine Regulation of Energy Metabolism by the Skeleton
Na Kyung Lee,1 Hideaki Sowa,1 Eiichi Hinoi,1 Mathieu Ferron,1 Jong Deok Ahn,3 Cyrille Confavreux,1 Romain Dacquin,4 Patrick J. Mee,5 Marc D. McKee,6 Dae Young Jung,7 Zhiyou Zhang,7 Jason K. Kim,7 Franck Mauvais-Jarvis,8 Patricia Ducy,2 and Gerard Karsenty1,*
1 Department of Genetics & Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
2 Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
3 CHO-A Biotechnology Research Institute, CHO-A Pharm. Co., Seoul 143-701, Korea
4 Ecole Normale Supérieure de Lyon, UMR5161, Laboratoire d'Endocrinologie Moléculaire et Différenciation Hématopoïétique et Osseuse, 69364 Lyon, France
5 Centre for Stem Cell Research, University of Cambridge, Cambridge CB2 1TN, United Kingdom
6 Faculty of Dentistry, and Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada H3A 2B2
7 Department of Cellular & Molecular Physiology, Penn State Medical Center, Hershey, PA 17033
8 Department of Medicine, Northwestern University School of Medicine, Chicago, IL 60611, USA
Copyright © 2007 Cell Press. All rights reserved.
Cell, Vol 130, 456-469, 10 August 2007
The regulation of bone remodeling by an adipocyte-derived hormone implies that bone may exert a feedback control of energy homeostasis. To test this hypothesis we looked for genes expressed in osteoblasts, encoding signaling molecules and affecting energy metabolism. We show here that mice lacking the protein tyrosine phosphatase OST-PTP are hypoglycemic and are protected from obesity and glucose intolerance because of an increase in ß-cell proliferation, insulin secretion, and insulin sensitivity. In contrast, mice lacking the osteoblast-secreted molecule osteocalcin display decreased ß-cell proliferation, glucose intolerance, and insulin resistance. Removing one Osteocalcin allele from OST-PTP-deficient mice corrects their metabolic phenotype. Ex vivo, osteocalcin can stimulate CyclinD1 and Insulin expression in ß-cells and Adiponectin, an insulin-sensitizing adipokine, in adipocytes; in vivo osteocalcin can improve glucose tolerance. By revealing that the skeleton exerts an endocrine regulation of sugar homeostasis this study expands the biological importance of this organ and our understanding of energy metabolism.
The full article is available online:
cell.com
Here is an article from The Scientist about the Cell article
Endocrine role for skeleton
Bone cell protein regulates insulin, says new study
By Amy Coombs
[Published 9th August 2007 06:58 PM GMT]
The skeleton functions as a part of the endocrine system and plays a role in regulating energy metabolism in the body, according to a study published this week in Cell.
"It's a sparkling observation," said Jake Kushner of the University of Pennsylvania in Philadelphia, who was not affiliated with the study. "The findings show that bone is an endocrine organ, and that it affects glucose homeostasis. This concept is totally novel."
The researchers showed that osteocalcin, a protein secreted by bone cells, regulates insulin production and insulin sensitivity in the body, answering a long-standing question about the protein's function. "Osteocalcin has been the flagship molecule of the bone field for decades," said Gerard Karsenty of the Columbia University Medical Center, the study's lead author. "It's the only molecule uniquely secreted by osteoblasts, but no one has been able to show what role it plays in the body."
Karsenty and colleagues first engineered osteocalcin knockout mice ten years ago. They noted that the mice were fatter than normal, but did not measure changes in blood sugar or other markers of energy metabolism.
In the current study, the researchers examined osteocalcin knockouts more closely. Despite being fed a normal diet, osteocalcin deficient mice had increased glucose levels and decreased insulin sensitivity, and developed type II diabetes. Mice engineered to produce excessive osteocalcin showed the opposite characteristics -- namely increased insulin production and greater insulin sensitivity.
In vitro studies confirmed that osteocalcin stimulates beta cells to produce insulin and promotes the growth of new beta cells in the pancreas. The researchers also found that osteocalcin signals fat cells to produce adiponectin, a metabolic hormone that regulates insulin sensitivity.
"That skeletal osteoblasts might now be involved in regulating glucose metabolism should lead to better understanding of diabetes, obesity, and energy metabolism," said Peter Hauschka of Harvard Medical School, who was not a co-author on the study.
The researchers' earlier work showed that leptin, a hormone secreted by fat tissue, inhibits bone formation. While mice lacking leptin are extremely obese, they are also protected against osteoporosis. The finding demonstrated that fat tissue signals bone, but no one has been able to show that bone cells talk back.
Because bone destroys and replaces itself every day -- a high energy process known as bone remodeling-it makes sense that the body's skeletal system must communicate with fatty energy preserves, said Karsenty. "If fat speaks to bone, bone must speak to fat," he said. "The surprise was finding that osteocalcin is the messenger."
The molecular mechanisms underlying this communication remain unknown. While the gene responsible for indirectly increasing osteocalcin activity is known, researchers do not understand how the post translational product results in hormone increases. Similarly, how osteocalcin stimulates insulin producing cells in the pancreas is unclear. "The big question is, how does it all work," said Kushner. "How does this bone specific mechanism influence beta cells to grow?"
Further studies will also have to explain why osteocalcin involved in glucose regulation is slightly different from the version traditionally found in bone. "It is the non-carboxylated fraction of osteocalcin that appears to play a regulatory role," said Haushka "yet most osteocalcin in the bone matrix is carboxylated."
It's possible that carboxylation is only performed by the body to trap osteocalcin in the bone, and that uncarboxylated proteins are used for other purposes. Answering these questions will shed more light on the protein's physiologic role, said Haushka.
Amy Coombs
mail@the-scientist.com
Links within this article:
N.K. Lee et al., "Endocrine regulation of energy metabolism by the skeleton,"
Cell, August 10, 2007.
cell.com
Jake Kushner
med.upenn.edu
J.B. Weitzman, "Shaping gene expression," The Scientist, February 20, 2002.
thescientist.com
A. Rinaldi, "Boning up on diabetes," The Scientist, June 23, 2003.
thescientist.com
Gerard Karsenty
cpmcnet.columbia.edu
T. Toma, "The link between obesity and diabetes," The Scientist, January 19, 2001.
thescientist.com
K. Grens, "New beta cells without stem cells?," The Scientist, May 29, 2007.
thescientist.com
Peter Hauschka
childrenshospital.org
E. Florent et al., "Leptin regulation of bone resorption by the sympathetic nervous system and CART," Nature, March 24, 2005.
the-scientist.com
S.J. Olshansky et. al., "What if humans were designed to last?" The Scientist, March 1, 2007.
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