While the effects of leptin on mice have been observed since 1950, the protein itself was not isolated until 1994. Leptin is expressed in adipose or fat tissue, and is also present in smaller amounts in the stomach, bone marrow, ovaries, pituitary gland, liver, and skeletal muscle.
Leptin concentrations in mice and in humans increase along with increases in body fat, and fasting and low calorie diets result in low leptin levels in the blood. Leptin and insulin both act as adiposity signals for the body. A very rare gene mutation of leptin in humans causes extreme hunger and results in severe obesity. This condition can now be treated using recombinant DNA techniques. Leptin is also involved in reproductive function. Prepubescent mice treated with leptin became thin and achieved reproductive maturity sooner than mice not treated with leptin. Humans with mutant forms of leptin both become obese and fail to develop reproductive maturity.
Leptin normally suppresses appetite, and this discovery led to great hopes for the development of an effective obesity treatment. When genetically normal mice, obese or thin, were injected with leptin, they ate less and lost weight.
“Everyone in the field thought they would get the Nobel," says Umut Ozcan, MD, of Children's Hospital of Boston, Division of Endocrinology. However, "Most humans who are obese have leptin resistance," says Ozcan. "Leptin goes to the brain and knocks on the door, but inside, the person is deaf."
This means that obese people have high levels of circulating leptin, but don’t feel its appetite suppression effects. This condition is similar to what happens with people with type 2 diabetes, who are resistant to the effects of insulin. This year, research has shown that obesity stresses the cells and blocks normal functioning, including leptin action in the brain. However, in mice, pretreatment with chemicals known as “chaperones” that assist with proper cell functioning, resulted in restored leptin sensitivity and weight loss. This weight loss occurred even when the mice were fed a hig-fat diet. Fortunately, the chemical chaperones used are already tested to be safe in humans and have FDA approval for clinical use. Current efforts are underway to develop human clinical trials with an eye towards weight loss applications.
Even more hopeful is a study released by the University of Florida that found that pairing leptin with a small amount of exercise revived leptin’s ability to fight fat in mice. Mice were divided into three groups, one of which was given leptin, another an exercise wheel, and one group received both. Obese rats lost weight with the combination of leptin and the wheel, while neither leptin nor exercise alone was effective in helping the mice lose weight. In fact, giving the mice leptin alone caused them to gain more weight than just eating a high-fat diet.
"[The mice] don't run enough to use sufficient energy to prevent weight gain," said Philip Scarpace, Ph.D., a professor of pharmacology and therapeutics in the UF College of Medicine and the senior author of the study. "What the act of running appears to do is allow the leptin to work again. It's a demonstration that this simple act can reverse leptin resistance."
Interestingly, the mice that lost the weight kept it off as well. The scientists speculate that the low level of activity somehow cleared a pathway for the leptin to work on the brain, because the mice didn’t run enough to make a significant difference in their weight. In fact, according to the researchers the mice were being fed a diet that should have caused them to gain weight even with the activity, so they can be certain the weight loss was due to the action of leptin.
If scientists can continue to improve leptin sensitivity, the potential for effective weight loss treatments becomes greater. Current research is also underway to understand the reasons why overweight people develop leptin resistance, so perhaps it can be prevented. However, as usual, the addition of exercise to anyone’s lifestyle seems to improve overall health and human functioning, so it is a safe recommendation to everyone.
