Contrary to the prevailing view, the hormone leptin, which is critical for normal food intake and metabolism, appears to regulate bone mass and suppress appetite by acting mainly through serotonin pathways in the brain, according to a recent study published in Cell by Yale School of Medicine researchers and colleagues at Columbia University. This new finding contradicts the view that leptin acts primarily in the hypothalamus.
"Our study challenges the view that the hypothalamus is the critical brain site where leptin acts directly to alter neuronal circuit function to suppress appetite and bone metabolism," said Yale researcher and study co-author Tamas Horvath. "We've now found a novel explanation for how leptin can act on the brain." Horvath is chair and professor of comparative medicine and professor of neurobiology and obstetrics & gynecology at Yale School of Medicine.
Food intake is influenced by signals that travel from the body to the brain. Leptin is one of the molecules that signal the brain to modulate food intake. It is produced in fat cells and informs the brain of the metabolic state. If animals are missing leptin, or the leptin receptor, they eat too much and become severely obese.
To determine whether leptin regulates bone mass through serotonin pathways, Horvath and his colleagues analyzed multiple lines of mice that were genetically altered to remove serotonin in the brain. "We found that when the serotonin pathway is turned off by leptin, the mice ate less, lost weight and their bones became weak. When the pathway is turned on, the mice ate more, gained weight and had more bone mass," said Horvath. "This might be why obese people tend to have much lower incidences of osteoporosis."
The study was designed by Gerard Karsenty of Columbia University as a follow-up to his groundbreaking work on the relationship between leptin and bone metabolism. Yale researchers provided a neurobiological framework for the study.
"This study modifies the map of leptin signaling in the brain and identifies a molecular basis for the common regulation of bone and energy metabolisms," said Horvath, who is also director of the recently established Program on Cell and Neurobiology of Energy Metabolism at Yale.
In addition to Horvath, senior author Karsenty and first author Vijay K. Yadav, other authors on the study included Franck Oury, Nina Suda, Zhong-Wu Liu, Xiao-Bing Gao, Cyrille Confavreux, Kristen C. Klemenhagen, Kenji F. Tanaka, Jay A. Gingrich, X. Edward Guo, Laurence H. Tecott, J. John Mann and Rene Hen.
Citation: Cell Vol. 138 809-1034