How Hunger Controlling Neurons Regulate Bone Mass

In an advance that helps clarify the role of a cluster of neurons in the brain, Yale School of Medicine researchers have found that these neurons not only control hunger and appetite, but also regulate bone mass.

The study is published Sept. 24 online ahead of print in the journal Cell Reports.

“We have found that the level of your hunger could determine your bone structure,” said one of the senior authors, Tamas L. Horvath, the Jean and David W. Wallace Professor of Comparative Medicine, and professor of neurobiology and obstetrics, gynecology, and reproductive sciences. Horvath is also director of the Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism.

“The less hungry you are, the lower your bone density, and surprisingly, the effects of these neurons on bone mass are independent of the effect of the hormone leptin on these same cells.”

Horvath and his team focused on agouti-related peptide (AgRP) neurons in the hypothalamus, which control feeding and compulsive behaviors. Using mice that were genetically-engineered so their cells selectively interfere with the AgRP neurons, the team found that these same cells are also involved in determining bone mass.

The team further found that when the AgRP circuits were impaired, this resulted in bone loss and osteopenia in mice — the equivalent of osteoporosis in women. But when the team enhanced AgRP neuronal activity in mice, this actually promoted increased bone mass.

Drawing of a neuron.
AgRP neurons not only control hunger and appetite, but also regulate bone mass, according to Yale researchers. Credit: Michael Helfenbein, Yale University.

“Taken together, these observations establish a significant regulatory role for AgRP neurons in skeletal bone metabolism independent of leptin’s action,” said co-senior author Karl Insogna, M.D., professor of medicine, and director of the Yale Bone Center. “Based on our findings, it seems that the effect of AgRP neurons on bone metabolism in adults is mediated at least in part by the sympathetic nervous system, but more than one pathway is likely involved.”

“There are other mechanisms by which the AgRP system can affect bone mass, including actions on the thyroid, adrenal and gonad systems,” Insogna added. “Further studies are needed to assess the hormonal control of bone metabolism as a pathway modulated by AgRP neurons.”

About this neurology research

Other authors on the study include Jae Geun Kim, Ben-Hua Sun, Marcelo O. Dietrich, Marco Koch, Gang-Qing Yao, and Sabrina Diano.

Funding: The study was supported by the National Institutes of Health, a Core Center award, and an ADA mentored Fellowship Award.

Source: Karen N. Peart – Yale
Image Source: The image is credited to Michael Helfenbein, Yale University
Original Research: Full open access research for “AgRP Neurons Regulate Bone Mass” by Jae Geun Kim, Ben-Hua Sun, Marcelo O. Dietrich, Marco Koch, Gang-Qing Yao, Sabrina Diano, Karl Insogna, and Tamas L. Horvath in Cell Reports. Published online September 24 2015 doi:10.1016/j.celrep.2015.08.070


Abstract

AgRP Neurons Regulate Bone Mass

Highlights
•Impaired AgRP neurons cause bone loss
•Enhanced AgRP neuronal activity increases bone mass
•Leptin receptors in AgRP neurons do not affect bone mass

Summary
The hypothalamus has been implicated in skeletal metabolism. Whether hunger-promoting neurons of the arcuate nucleus impact the bone is not known. We generated multiple lines of mice to affect AgRP neuronal circuit integrity. We found that mice with Ucp2 gene deletion, in which AgRP neuronal function was impaired, were osteopenic. This phenotype was rescued by cell-selective reactivation of Ucp2 in AgRP neurons. When the AgRP circuitry was impaired by early postnatal deletion of AgRP neurons or by cell autonomous deletion of Sirt1 (AgRP-Sirt1−/−), mice also developed reduced bone mass. No impact of leptin receptor deletion in AgRP neurons was found on bone homeostasis. Suppression of sympathetic tone in AgRP-Sirt1−/− mice reversed osteopenia in transgenic animals. Taken together, these observations establish a significant regulatory role for AgRP neurons in skeletal bone metabolism independent of leptin action.

“AgRP Neurons Regulate Bone Mass” by Jae Geun Kim, Ben-Hua Sun, Marcelo O. Dietrich, Marco Koch, Gang-Qing Yao, Sabrina Diano, Karl Insogna, and Tamas L. Horvath in Cell Reports. Published online September 24 2015 doi:10.1016/j.celrep.2015.08.070

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