Researchers have uncovered a destructive mechanism at the molecular level that causes a well-known phenomenon associated with obesity: leptin resistance. They found that mice fed a high-fat diet produce an enzyme named MMP-2 that clips receptors for the hormone leptin from the surface of neuronal cells in the hypothalamus. This blocks leptin from binding to its receptors. This, in turn, keeps the neurons from signaling that your stomach is full and you should stop eating.
They found that mice fed a high-fat diet produce an enzyme named MMP-2 that clips receptors for the hormone leptin from the surface of neuronal cells in the hypothalamus. This blocks leptin from binding to its receptors.
This, in turn, keeps the neurons from signaling that your stomach is full and you should stop eating. Scientists showed that when MMP-2 is blocked, leptin can still bind to the receptors and signal satiety.
Breakdown Of An Enzyme
They hope that in the future, clinicians will be able to treat leptin resistance in humans by blocking MMP-2. They also have evidence that their findings have a broader scope. They hypothesized that an enzyme breaking down proteins into amino acids and polypeptides can cleave membrane receptors and lead to dysfunctional activity.
Leptin Molecules
When you block the protease that leads to the receptors not signaling, you can treat the issue. Leptin molecules are released from white fat tissue during a meal. They travel through the bloodstream into the brain, specifically the hypothalamus, where they stimulate neural receptors to signal that the stomach is full.
Leptin resistance is a known process associated with obesity, but the molecular mechanisms by which it occurs were not understood. Researchers first tested brain tissue from obese mice for protease activity. This is how they found MMP-2, the enzyme that they suspected was damaging leptin receptors.
Leptin Receptors
They developed a method to tag leptin receptors to see what was happening to them. They observed that MMP-2 was damaging the receptors, which lost their ability to signal.
Recombinant Protein
Researchers then used a recombinant protein to verify that the MMP-2 enzyme was indeed cleaving leptin receptors. They also cultured brain cells from mice and found clipped receptors when MMP-2 was present.
Researchers genetically altered a group of mice not to produce MMP-2. In spite of being fed a high-fat diet, these mice gained less weight, and their leptin receptors remained intact. Meanwhile, mice that were fed the same diet but were not genetically altered became obese, and their leptin receptors were cleaved.
In the long run, researchers aim to design an MMP-2 inhibitor or an inhibitor for the MMP-2 pathway of activation. Next steps also include confirming that the same mechanism occurs in human brain cells.
In the future, they will try to find out why proteases are activated, what is activating them and how to stop it. They think that other membrane receptors may also be destroyed in the same way. There is still a lot of work to do to better understand receptor cleaving and the loss of cell function while on a high-fat diet