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.
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Explore This IssueApril 2010
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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.