A protein that interferes with the brain's attempts to "turn off" the sensation of hunger may be the key in developing a drug for impeding weight gain
Morbid obesity is a serious concern in the Western world. A recent study, led by two Israeli researchers – Rafi Mazor from the University of California, San Diego and Dinorah Friedmannn-Morvinski from Tel Aviv University – found that inhibiting a specific protein reduced the tendency of rats on a high-fat diet to gain weight.
The study focused on a hormone called leptin, which is secreted from fat tissue and, when it binds to its receptor, induces the sensation of fullness that encourages us to stop eating. Leptin receptor malfunction has been found in many obese individuals who consume a high-fat diet, since it interferes with their ability to lose weight and decrease their food intake. Thus, obesity cannot simply be treated by administering leptin.
A short-termed high-fat diet also leads to an increase in the activity of the protein MMP-2, which can cut, or cleave, other proteins. Moreover, it was found that in the absence of this protein, a high-fat diet does not lead to extreme weight gain. Based on this, the current study was guided by the hypothesis that the elevated activity of this protein in people who consume a high-fat diet leads to cleavage of leptin receptors. When these receptors stop functioning, the sense of fullness is lost, and there is nothing to stop us from eating more.
Obesity was induced in rats by providing them with a high-fat diet for 12 weeks, while comparing them to rats consuming normal food. As expected, the obese rats gained weight, but more importantly, the number of their leptin receptors was reduced by half, while the activity of MMP-2 was increased 2.5-fold.
These findings are not sufficient, of course, to conclude a causal relationship between MMP-2 activation and cleavage of the receptor. In order to confirm or debunk the existence of such a relationship, the researchers worked with a culture of cells from the hypothalamus, the brain region that governs hunger and fullness sensations, among other functions. They added active MMP-2 to the cells, which contain the leptin receptor, and found that the MMP-2 treatment resulted in a decrease over 20% in leptin receptor quantity, a clear indication that the protein, in fact, cleaved the receptor.
Next, to test whether the cleavage also affects the receptor’s function, the researchers looked into the chemical reactions that take place as leptin binds to its receptor. They found that in the presence of MMP-2, the fullness hormone leptin is less effective in activating its receptor, leading to the conclusion that leptin receptor cleavage by MMP-2 indeed negatively affects its function.
To link the two observations and confirm that MMP-2 activation induced by consuming a high-fat diet is what causes the leptin receptor malfunction, the researchers generated mice that lack MMP-2 throughout their body. When given a high-fat diet, these mice gained less weight than normal mice and had a larger number of leptin receptors, like the mice on a normal diet. It appears that the lack of MMP-2 counters the effects of a high-fat diet.
The study demonstrates that MMP-2 may serve as a target for treating morbid obesity in humans, one of the greatest modern-world pandemics. But one problem with this target is that MMP-2 deficiency in the entire body may be detrimental: engineered mice lacking this protein, such as the ones in the study, have lower birth weight and a slower growth rate. Therefore, an efficient treatment for obesity would possibly be a drug that inhibits this protein's activity only in the hypothalamus – where the negative effects of the high-fat diet take place. Until the magic pill for obesity will be found, we will just have to maintain a healthy, balanced diet.
Translated by Elee Shimshoni