Philadelphia—Discovery of a leptin–serotonin pathway to regulate appetite and bone mass accrual is providing valuable insight into bone disease and may open new pathways to therapy.
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Explore This IssueApril 2010
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Gerard Karsenty, MD, PhD, chair of the department of genetics and development at Columbia University’s College of Physicians and Surgeons in New York, said that this research is a good example of how physiology “has been more changed by mouse genetics than any other field.” He delivered the Hench Society Lecture here at the ACR/ARHP Annual Scientific Meeting in October 2009. Each year, the Hench Society Lecture honors the contributions of Philip S. Hench, MD, the co-winner of the 1950 Nobel Prize in Medicine, for his work on cortisone.
In his lecture, Dr. Karsenty reviewed several steps in the research with mouse models that were published in the journal Cell.1 This research, he said, underscored the concept that, “for every physiological function, there is more than one organ involved.”
Although clinical applications await future investigation, the current research adds to understanding of the apparent association of obesity with a lower incidence of osteoporosis. It may open up new avenues for research into the development of osteoporosis in people treated with selective serotonin reuptake inhibitors (SSRIs). Dr. Karsenty noted two important clinical observations that prompted this avenue of research: “Obesity invariably follows gonadal failure, and obesity protects from osteoporosis.”
Understanding Bone Remodeling
Research conducted by Dr. Karsenty and colleagues in 2007 had identified the skeleton as an organ of the endocrine system that helps regulate glucose metabolism. In that research, also published in Cell, they reported that bone cells release osteocalcin.2 “By revealing that the skeleton exerts endocrine regulation of sugar homeostasis, this study expands the biological importance of this organ and our understanding of energy metabolism,” they wrote.
According to Dr. Karsenty’s presentation at the meeting, there are two defining features of the physiology of the skeletal system. One is that the skeleton, with the skin and muscle, is an organ covering the largest surface of the body. Additionally, and somewhat surprisingly, bone contains a cell, the osteoclast, whose main function is to constantly destroy bone.
It is now understood that leptin regulates the homeostatic function of bone remodeling in humans and in mice, a process that includes both bone resorption and bone formation. The original purpose of bone remodeling during evolution was the repair of micro and macro damage, or fractures. “It was a survival function,” Dr. Karsenty said.
However, bone remodeling also requires energy expenditures for both the osteoclasts and the osteoblasts. Thus, an early hypothesis was that bone mass, appetite, and reproduction may be controlled by the same hormones. Only leptin has been identified as the hormone involved in all three. “Leptin is an adipocyte-derived hormone identified for its ability to regulate energy metabolism and reproduction. It appears during evolution much later than energy metabolism and signals in the brain to fulfill its functions,” he said.
Leptin deficiency has many facets, he said, including behavioral abnormalities, small size of the brain, wound-healing defects, immunity defects, and low sympathetic tone. Reflex sympathetic dystrophy is a disease characterized by localized high sympathetic activity and bone loss. This condition has been successfully treated with beta-blockers.
Function of Leptin
Researchers had several central questions about the function of leptin. “Where does leptin signal in the brain to regulate bone mass accrual? Where does leptin signal in the brain to regulate energy metabolism? Is there a common molecular basis between these two functions of leptin?” Dr. Karsenty listed.
Through research with several mouse models, Dr. Karsenty and colleagues have found that serotonin is the molecular basis of the central coregulation of bone mass and energy metabolism. It is leptin that regulates these two functions by acting in the brainstem and by inhibiting synthesis and release of serotonin. “Leptin inhibits bone mass accrual, and this function occurs independently of its ability to regulate energy metabolism. This function also occurs only through a central relay,” Dr. Karsenty said.
As explained in the research published in Cell, serotonin is produced in cells of the duodenum and in serotonergic neurons of brainstem and does not cross the blood–brain barrier. Because of this mode of production, serotonin is a molecule “with two distinct functional identities depending on its site of synthesis: a hormone when made in the gut and a neurotransmitter when made in the brain.”1
Those roles had been previously known, but serotonin’s role in bone mass had not been identified. Dr. Karsenty and colleagues showed that brain-derived serotonin favors bone mass accrual and appetite, unlike leptin. It is leptin that regulates those functions by inhibiting serotonin synthesis in the neurons of the brainstem.
Mouse Models Instrumental
A series of mouse models were critical to this research, Dr. Karsenty said. For example, one mouse model was unable to synthesize serotonin anywhere in its body. By using this mouse model, the researchers hoped to ascertain the contribution of the brain-derived serotonin on regulation of bone mass accrual. These mice had a low bone mass, a decrease in bone formation, and an increase in bone resorption, thus indicating the role that the brain-derived serotonin has in regulation of bone mass.
Use of another mouse model indicated that bone mass accrual through brain-derived serotonin occurs by a decrease in sympathetic tone. The brain-derived serotonin apparently uses the Htr2c receptor—the most abundant serotonergic receptor in the hypothalamus—that mediates brain serotonin regulation of bone mass, a function that is independent of its influence through the same receptor on energy metabolism, the researchers reported in Cell.
Studies using a different mouse model indicated that brain-derived serotonin acts on ventromedial hypothalamic neurons through Htr2c “to decrease sympathetic activity and to favor bone mass accrual,” Dr. Karsenty said.
Dr. Karsenty and colleagues reported that their understanding of regulation of bone mass by serotonin led to unexpected observations. First, “depending on its site of synthesis, serotonin regulates bone mass accrual in opposite directions: it inhibits it when synthesized in the duodenum and favors it when acting as a neurotransmitter.”1 They noted that this seems to be the first example of a molecule that has different influences on bone remodeling that is dependent on the site of synthesis.
The second unexpected observation was that, even though brain-derived serotonin represents only about 5% of the total pool of serotonin in the body, its influence on bone remodeling “is dominant over that exerted by gut-derived serotonin. Since [brain-derived serotonin] is regulated by leptin, these results infer that leptin regulation of bone mass is more important than the one exerted by gut-derived serotonin.”
Based on that observation, the researchers predict that “using leptin as a treatment for obesity would favor the appearance of osteoporosis.”1
Kathy Holliman is a medical journalist based in New Jersey.