By meticulously mapping the 3D structure of the hormone leptin and its receptor, researchers from the Flemish Institute of Biotechnology (VIB) have revealed how the so-called ‘satiety hormone’ binds. The discovery could lead to new approaches to treating obesity, a major risk factor for the development of diabetes and cardiovascular disease.
Leptin is produced in the gastric mucosa. When leptin levels are high, our brain gets the signal that our energy reserves are sufficient and that we don’t need to eat. In other words, we feel full. That “I’m full” signal is passed on when the hormone binds with a leptin receptor (LEP-R) on the surface of brain cells.
Researchers from the VIB-UGent Center for Inflammation Research collaborated with colleagues from the University of Osnabruck in Germany and the Belgian biotechnology company PUXANO. Using X-ray crystallography and cryo-electron microscopy, the researchers created a 3D representation of the binding between the hormone and the receptor to near-atomic resolution. For example, they discovered that leptin induces a unique type of receptor assembly and undergoes structural changes that enable its binding to LEP-R
“The molecular organization of the leptin:LEP-R assembly has taken us completely by surprise,” says Dr. Kenneth Verstraete, who led the research with Prof. Savvas Savvides. “It is built by three leptin molecules connecting three receptor molecules, which provides important new insights for understanding how leptin works.”
Dr. Alexandra Tsirigotaki, the study’s first author, emphasizes that leptin mutations are associated with severe obesity. “Our findings now explain such clinically important mutations and will be an important resource for the scientists studying leptin signaling.”
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