Decoding the satiety signal

Research reveals how leptin and its receptor work together to regulate hunger signals

Leptin trimer.jpg

The protein hormone leptin signals our brains that we are full and can stop eating. To send that signal, leptin has to bind to a receptor on the cells that need to receive the message. Researchers at the VIB-UGent Center for Inflammation Research, collaborating with colleagues at Osnabruck University (Germany) and the Belgian biotechnology company PUXANO, have now revealed how leptin and its receptor work together. Their arresting research results appear in the leading scientific journal Nature Structural & Molecular Biology and may spark new approaches in treating obesity, a major metabolic condition worldwide.

The satiety hormone

In 1994, the American scientist Jeffrey Friedman discovered the hormone leptin. He wanted to understand why some lab mice strains could not stop eating. Eventually, he zeroed in on leptin, now also known as the satiety hormone, which regulates body weight and other biological processes involved in immunity, fertility, and cancer, for example.

Leptin is made by white fat cells and the gastric mucosa. When the leptin levels are high, our brains receive the signal that our energy stores are sufficient and we don't need to eat. We feel full, in other words. That 'I'm full' signal is passed along by leptin when it binds to the leptin receptor (LEP-R) on the surface of brain cells.

Dr. Kenneth Verstraete, who led the research with prof. Savvas Savvides (VIB-UGent Center for Inflammation research): "The receptor for Leptin has six different forms with varying activity levels. The longest form of the receptor can send signals to the brain and is linked to energy balance and food intake. The leptin-receptor assembly took us completely by surprise! It is constructed by three leptin molecules connecting three receptor molecules, which offers important new insights to understand how leptin functions."

Visualizing the leptin-LEP-R receptor complex

The researchers used X-ray crystallography and Cryo-Electron Microscopy to determine the 3D-structure of the leptin- LEP-R assemblies to near-atomic resolution and single-molecule tracking to confirm such complexes on living cells. Such an innovative combination of methods was critical to the project's success. The researchers found that leptin induces a unique type of receptor assembly and undergoes structural changes that activate its binding to LEP-R.

Dr. Alexandra Tsirigotaki, first author of the study: "We know that specific mutations in leptin and the leptin receptor are associated with severe obesity. Our findings now explain such clinically important mutations and will be an important resource for the large community studying leptin signaling in basic and clinical science."

This new understanding of how leptin interacts with its receptors at the cell surface has important implications for understanding how the hormone works in the body.

Prof. Savvas Savvides: "Collectively, our work will help to consolidate two decades of research on the role of leptin in physiology and disease and will catalyze the development of treatments for leptin dysfunction and the creation of new variants of leptin with improved properties."


Mechanism of receptor assembly via the pleiotropic adipokine Leptin. Tsirigotaki et al. Nature Structural & Molecular Biology, 2023.

Gunnar De Winter

Gunnar De Winter

Science Communications Expert, VIB



About VIB

VIB’s core mission is to generate disruptive insights in the molecular underpinning of life and to translate these actively into impactful innovations for patients and society. VIB is an independent research institute where some 1,800 top scientists from Belgium and abroad conduct pioneering basic research. As such, they are pushing the boundaries of what we know about molecular mechanisms and how they rule living organisms such as human beings, animals, plants, and microorganisms. Based on a close partnership with five Flemish universities – Ghent University, KU Leuven, University of Antwerp, Vrije Universiteit Brussel, and Hasselt University – and supported by a solid funding program, VIB unites the expertise of all its collaborators and research groups in a single institute. VIB’s technology transfer activities translate research results into concrete benefits for society such as new diagnostics and therapies and agricultural innovations. These applications are often developed by young start-ups from VIB or through collaborations with other companies. This also leads to additional employment and bridges the gap between scientific research and entrepreneurship. VIB also engages actively in the public debate on biotechnology by developing and disseminating a wide range of science-based information. 

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