The implementation of glucagon-like peptide-1 (GLP-1)-based drugs for the treatment of obesity has been an incredible advance in the field, enabling up to 25% decreases in body weight in many patients. However, GLP-1 is only one of many factors in the body that regulate appetite. So why are some of these other hormones not also being used to treat overweight and obesity? The answers are sometimes surprising, as exemplified by the focus today on leptin.
One of the first hormones found to inhibit appetite and decrease body weight was leptin. Named leptos after the Greek word meaning ‘thin’, the gene for leptin was cloned by Jeffrey Friedman at Rockefeller University in 1994. To do this, he used a new molecular technique (positional cloning) to identify the mutated gene in a mouse model of massive obesity, called the ob/ob mouse. These mice demonstrate insatiable appetites leading to massive obesity (think ~3-times normal body weight) and, curiously, are also largely infertile. However, Dr. Friedman also discovered that leptin is mainly expressed in the white fat (adipose) tissue in the body, but not in the brain where appetite is regulated.
So how does leptin act to decrease appetite? The main effect is mediated by passage of leptin from the blood into the brain, where it acts to inhibit neural peptides that increase appetite (such as neuropeptide Y), and to stimulate neural peptides that decrease appetite (such as alpha-melanocyte stimulating hormone). Furthermore, administration of leptin to ob/ob mice, which have inactivating mutations in both copies of the leptin gene, inhibited their appetite leading to profound weight loss, and also increased their fertility.
The discovery of leptin engendered tremendous interest, not only in the scientific community, but also from the pharmaceutical industry, as it was believed that administration of leptin to those living with overweight or obesity would cause them to lose weight. And, indeed, this is true for humans who, like the ob/ob mouse, are completely leptin deficient. Children with two copies of a leptin mutation suffer from morbid obesity due to a lack of appetite suppression and, like the ob/ob mouse, fail to enter puberty – when treated with leptin, they lose weight and gain reproductive capabilities. However, such leptin mutations are actually exceedingly rare, with only a handful of such individuals identified globally. Furthermore, there are also very rare individuals who have two copies of mutations in the receptor for leptin – these individuals are complete unresponsive to leptin (like the so-called db/db mouse and fa/fa rat models of obesity) and, unfortunately, cannot even be treated with leptin. But what about the greater than 40% of the world’s population that currently suffers from overweight or obesity that is not associated with mutations in the leptin signaling pathway?
As a hormone that is expressed by the white adipose tissue, leptin levels in the blood rise in direct proportion to the amount of body fat. Thus, paradoxically, the greater the obesity, the more leptin is found in the blood. This should actually decrease appetite, in a so-called negative feedback loop, whereby increased fat results in increased leptin which then suppresses appetite resulting in decreased body fat. Unfortunately, this regulatory system becomes impaired in obesity, as the higher the leptin levels in the blood, the more resistant the brain becomes to the actions of leptin. As a result, appetite is not suppressed by the high levels of leptin in obesity, nor is administration of even more leptin effective in reducing body weight.
While this was a major blow to big pharma, as well as to those living with obesity, the discovery of leptin has increased our understanding of several biological systems. First, in normal physiology, leptin does play a role in the regulation of appetite and, hence body weight, through its connection of the white adipose tissue to the feeding centres of the brain. But, as part of this system, the discovery of leptin has also provided insight into the regulation of the human reproductive system. Hence, when fat mass falls below normal, leptin levels in the blood also fall. This results in a signal to the brain to increase appetite, as part of the normal feedback loop, but also to reduce fertility, through loss of the leptin signal to the neurons in the brain that control reproduction. In other words, if the body has insufficient fat mass to support reproduction, then fertility is reduced. Conversely, when fat mass is sufficient to support the growth needs of a fetus and infant, then leptin levels rise and the reproductive pathway is enabled. The elucidation of this relationship between fat mass, leptin and reproduction helps to explain, at least in part, why many extremely fit athletes, individuals with anorexia or those suffering from famine have reduced fertility, at least from an evolutionary perspective.
In contrast to the success of GLP-1-based drugs for the treatment of overweight and obesity, the story of leptin has been one of disappointment from the global perspective, albeit tremendously successful for the limited number of leptin-deficient patients around the world. However, the biology of appetite regulating hormones is still being intensely studied and, given the complexity of the feeding regulatory system, it remains possible that yet more discoveries are still pending.
Patricia Brubaker, Ph.D., F.R.S.C., F.C.A.H.S. is a Professor Emerita, Departments of Physiology and Medicine and a Banting & Best Distinguished Scholar at the University of Toronto, Toronto, ON, Canada. Dr. Brubaker completed both her undergrad and PhD at 91ÉçÇø.
