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A Molecular Reason Why Obese People Have Trouble Losing Weight

Obesity rates in the U.S. and abroad have soared: The world now has more overweight people than those who weigh too little. One reason relates to the way the body reacts to its own fat stores by setting in motion a set of molecular events that impede the metabolic process that normally puts a damper on hunger.

A new study published August 22 in Science Translational Medicineprovides details of how this process occurs, giving new insight into why obese individuals have trouble shedding pounds. It also suggests a possible treatment approach that targets obesity in the brain, not in the belly.

Scientists have long known that a hormone called leptin is instrumental in regulating the human diet. Produced by fat cells, the molecule communicates with a brain region called the hypothalamus, which reins in hunger cravings when our energy stores are full.

Yet as we gain weight our bodies become less sensitive to leptin, and it becomes harder and harder to slim down. In other words, weight gain begets more weight gain. In an experiment using mice that became obese on a high-fat diet, an international team found obesity increases the activity of an enzyme called matrix metalloproteinase-2, or MMP-2. By using a technique called western blot analysis—separating and identifying all the proteins in a tissue sample—the authors found MMP-2 cleaves off a portion of the leptin receptor in the hypothalamus, impairing the hormone’s signaling and its ability to suppress appetite.

The study also revealed that disabling MMP-2 with a gene-silencing technique—one in which a stretch of RNA was injected directly into the hypothalamus—had the effect of reducing weight gain in obese mice and preventing leptin receptor cleavage. Conversely, viral delivery of MMP-2 to the same brain region promoted subsequent weight gain and the snipping off of receptors. “The concept of ‘leptin resistance’ was already known in the field,” says paper co-author Dinorah Friedmann-Morvinski, a cell biologist at Tel Aviv University in Israel. “Our contribution to the field is (revealing) this mechanism by which obesity induces the activation of MMP-2 in the hypothalamus, which impairs the subsequent leptin-signaling cascade.”

Friedmann-Morvinski and her colleagues—including lead author Rafi Mazor, a biologist at the University of California, San Diego—also found treating hypothalamic cells in a lab dish with inflammatory compounds increases the expression of the MMP-2 gene, suggesting the initial “cause” of obesity results from inflammation. Previous research supports the idea high-fat, high-calorie diets can induce chronic low-grade inflammation of the hypothalamus, which over time may escalate MMP-2 production.

Martin Myers, a diabetes researcher and professor of internal medicine at the University of Michigan (U.M.) who was not involved with the work, agrees MMP-2 is probably playing a role in energy balance. He points out, however, the new study is not enough to demonstrate that it interferes with leptin signaling in living animals. “I think their finding about a role for MMP-2 in the [hypothalamus] is potentially important. But I don’t think they have identified the mechanism,” he says. “I think the most important problem here is that they have not shown any alteration of [leptin] signaling in vivo.”— a contention disputed by the study’s authors.

If the new findings do pan out, they could open the door to possible therapies aimed at damping down inflammation in the brain, decreasing MMP-2 activity and boosting the brain’s responsiveness to leptin. “The therapeutic implications here are far-reaching,” says Friedmann-Morvinski. “They point to inflammation as one important player in obesity, and also suggest targeting MMP-2 could be a novel strategy to tackle the problem.”

The challenge, however, will be to develop such a treatment in humans in whom regular hypothalamic injections are not possible. Mazor’s team hopes to identify a drug—possibly encapsulated inside a nanometer-scale particle — that can reach the hypothalamus and specifically block MMP-2 activity. And if that’s too narrow a target, they plan to assess the effects of reducing MMP-2 more globally in the brain.

This line of research has generated keen interest. A study published in Science Advances on August 22 by researchers at the U.M. and Vanderbilt University found proteins that act as a form of “energy rheostat,” which ensure neither too much nor too little food is consumed, suggesting another new target for new anti-obesity drugs.

The costs of the obesity epidemic are countless. Being substantially overweight increases the risk of conditions like heart disease, diabetes, sleep disorders and high blood pressure. And according to a recent study conducted by Harvard T. H. Chan School of Public Health, the cost of weight-related medical problems is now over $190 billion a year in the U.S. A true diet pill—a safe treatment that could control appetite in people prone to problem eating—would find ready demand among the millions who struggle to lose excess pounds.



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