New research from Columbia University Medical Center has illuminated a previously unknown leptin-serotonin pathway in the brain that simultaneously promotes appetite and bone mass accrual. The research, which explains how leptin – well-known appetite-suppressing hormone – acts in the brain, is published in the Sept. 4 issue of Cell.
When the leptin-serotonin pathway is turned on in mice, the researchers found, appetite increases, the animals eat more, gain weight, and their bone mass increases. When the pathway is turned off, mice eat less, lose weight, and their bones weaken. Furthermore, leptin was found to not act in the hypothalamus as previously thought, but in the brain stem acting on serotonin, a hormone that in the brain acts to control appetite, mood and anger.
The identification of this pathway helps explain why, as doctors have long known, obese people tend to have a significantly lower prevalence of osteoporosis, says the study's senior author, Gerard Karsenty, M.D., Ph.D., chair of the Department of Genetics & Development at Columbia University's College of Physician and Surgeons. Though obese people produce high levels of leptin, they are resistant, or unresponsive, to its signals – instead, they operate in a false state of leptin deficiency, which increases serotonin – and thereby, appetite and bone mass. Dr. Karsenty points out that these current findings may have more influence on developing a new way to reduce appetite and obesity than preventing osteoporosis.
"It will be difficult to turn on the pathway to strengthen bone without increasing appetite at the same time," Dr. Karsenty said. "But this finding shows that it is feasible to alter parts of the leptin-serotonin pathway to decrease appetite without weakening bone."
HORMONE LEPTIN SUPRESSES BONE FORMATION BY SHUTTING OFF SEROTONIN
Dr. Karsenty and his colleagues discovered this pathway after first noticing the powerful effect of leptin – known for suppressing appetite – on bone mass accrual. Dr. Karsenty previously discovered that leptin is the most powerful inhibitor of bone formation in the body. This new study reveals that high levels of leptin suppress bone formation by shutting off the synthesis of serotonin in certain neurons in the brainstem.
Dr. Karsenty and his colleagues were surprised to observe that increased serotonin in the brainstem also increased appetite in mice. "We previously thought that leptin's modes of action on appetite and bone mass accrual were distinct," Dr. Karsenty said. "But we found instead that they behave more like twins – taking the same pathway through the brainstem. This correlates strikingly with the fact that leptin appears during evolution of bone cells when bone is first formed in the body."
Dr. Karsenty's team found that the appetite and bone pathways diverge once serotonin is released: one set of serotonin receptors turns on appetite, while a second increases bone mass accrual.
The findings may open the door for weight loss drugs that have no side effects on bone density.
"Theoretically, one can imagine that a drug that blocks only the appetite receptors, but not the bone receptors, could help people lose weight without losing bone mass," Dr. Karsenty said.
Dr. Karsenty explained the surprising link between appetite and the skeleton by noting that the pathway monitors the amount of energy available to maintain bone.
"Our bones are constantly broken down and rebuilt during our lifetimes, and those renovations require an enormous and daily supply of energy," he said.
DISCOVERY CLARIFIES PREVIOUS RESEARCH; ADDS TO WORK ON BONE
In November 2008, Dr. Karsenty published a paper in Cell, which describes how serotonin released from the gut controls bone formation. Unlike the brain's serotonin, an increase in gut serotonin impairs bone formation. (A press release about the Nov. 2008 finding is available at: http://www.cumc.columbia.edu/news/press_releases/Karsenty-cell-serotonin-lrp5.html.)
Dr. Karsenty's new research shows that while both derivations of serotonin influence bone mass, the brain's serotonin dominates the effect of serotonin from the gut.
LEPTIN-SEROTONIN PATHWAY MAY ALSO EXPLAIN OSTEOPOROSIS/ANTI-DEPRESSANT LINK
In some studies, selective serotonin reuptake inhibitors (SSRIs), which are commonly used to treat depression, have been associated with osteoporosis in some patients.
SSRIs enhance the action of serotonin, and depending on the person, that may lead to weakened, or strengthened bones, says study co-author J. John Mann, M.D., Ph.D., professor of translational neuroscience (in psychiatry and in radiology) and vice chair for Research in the Department of Psychiatry at Columbia University Medical Center and the New York State Psychiatric Institute.
"SSRIs work in the brain and in the gut, but in some people they may work more strongly in the gut," Dr. Mann said. "In that case, SSRIs could lead to a decrease in bone growth and osteoporosis."
The hope is that these research findings will help explain this phenomena and lead to potential treatment for this side effect.
Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future health care leaders at the College of Physicians & Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians & Surgeons was the first in the country to grant the M.D. degree. Columbia University Medical Center is home to the largest medical research enterprise in New York City and state and one of the largest in the United States.
Elizabeth Streich | EurekAlert!
Newly designed molecule binds nitrogen
23.02.2018 | Julius-Maximilians-Universität Würzburg
Atomic Design by Water
23.02.2018 | Max-Planck-Institut für Eisenforschung GmbH
A newly developed laser technology has enabled physicists in the Laboratory for Attosecond Physics (jointly run by LMU Munich and the Max Planck Institute of Quantum Optics) to generate attosecond bursts of high-energy photons of unprecedented intensity. This has made it possible to observe the interaction of multiple photons in a single such pulse with electrons in the inner orbital shell of an atom.
In order to observe the ultrafast electron motion in the inner shells of atoms with short light pulses, the pulses must not only be ultrashort, but very...
A group of researchers led by Andrea Cavalleri at the Max Planck Institute for Structure and Dynamics of Matter (MPSD) in Hamburg has demonstrated a new method enabling precise measurements of the interatomic forces that hold crystalline solids together. The paper Probing the Interatomic Potential of Solids by Strong-Field Nonlinear Phononics, published online in Nature, explains how a terahertz-frequency laser pulse can drive very large deformations of the crystal.
By measuring the highly unusual atomic trajectories under extreme electromagnetic transients, the MPSD group could reconstruct how rigid the atomic bonds are...
Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...
For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.
In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
23.02.2018 | Physics and Astronomy
23.02.2018 | Health and Medicine
23.02.2018 | Physics and Astronomy