Microscope photo of adipose tissue. Credit: jxfzsy/iStock/Getty Images Plus
Discovered more than 2 decades ago, the hormone leptin has been widely hailed as the key regulator of leanness. Yet, the pivotal experiments that probe the function of this protein and unravel the precise mechanism of its action as a guardian against obesity are largely missing. Flier, the HMS George Higginson Professor of Physiology and Medicine, and Maratos-Flier, HMS professor of medicine at Beth Israel Deaconess Medical Center, have made significant contributions to the understanding of the metabolism of obesity and starvation in general, and of leptin in particular.
The commentary highlights what the authors say is a startling lack of experimental evidence detailing the biologic roles of leptin in metabolism, and calls for a renewed effort to characterize the action of the hormone. “It’s been assumed—but never shown—that leptin helps keep lean people lean, staving off weight gain,” Flier said. 22 years ago, researchers discovered the identity of a mouse obesity gene and found that it encodes a previously unknown hormone made by fat cells, which they named leptin, a term derived from the Greek word for leptos for “slim.” In a rare genetic deficiency, people born with two defective copies of the gene are extremely obese, and their obesity can be reversed by restoring their leptin levels with daily injections.
In mice and in people without the mutation, studies have shown that leptin plays an important role in regulating metabolism—just not the one it’s most famous for—obesity prevention. Studies from the Flier lab first showed that falling leptin levels signal the body that it may be in danger of starvation. The role for leptin as a starvation signal is now well established. Early on, researchers speculated that this protein might also play a key role in helping healthy lean people remain thin, perhaps by serving as a signal that orchestrates resistance to obesity. Paradoxically, obese mice and people who don’t have the defective obesity gene almost always have high levels of leptin. Flier first hypothesized that this may be due to some kind of leptin resistance, analogous to the insulin resistance seen in type 2 diabetes.
While some leptin is clearly necessary to prevent obesity the role of leptin in most individuals may be limited to signaling the response to hunger or starvation, and then reversing that signal as energy stores are restored, as they first hypothesized more than 20 years ago. If that is true, the biology of leptin has little to do with leanness or obesity, apart from a few rare cases of primary deficiency with severe obesity. Obesity fuels a range of chronic diseases, including diabetes, high blood pressure, liver disease, kidney damage, arthritis and cardiovascular disease, among others. More than $140 billion is spent each year in the US to treat obesity-related diseases, according to the CDC. Worldwide obesity rates have doubled since 1980, and most people now live in countries where more deaths are caused by overweight and obesity than by malnourishment, according to the World Health Organization.
The authors note that it’s possible, even likely, that as-yet undiscovered molecules, not leptin, mediate the regulation of body weight and its dysregulation in obesity. Treatment with leptin was approved in the US in 2014 for use in congenital leptin deficiency as well as in an unusual syndrome of lipodystrophy, but the protein has not been readily available for clinical experiments.
The authors propose a clinical study measuring how lean people respond to increased leptin levels. If leptin is an anti-obesity hormone, it might suppress hunger or increase energy expenditure in trial participants compared to those who get a placebo. “We continue to believe that healthy and lean individuals exist who resist obesity at least in part through their leptin levels, and that some individuals develop obesity because they have insufficiently elevated leptin levels or cellular resistance to leptin,” Flier said. “But in science, belief and knowledge are two different things, and as much as we may lean toward this belief, we ought to develop evidence for this hypothesis or abandon it in favor of new potential mechanisms for the regulation of body weight.” https://medicalxpress.com/news/2017-06-decades-discovery-anti-obesity-hormone-scant.html
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