In 1994, Dr. Jeffrey Friedman, a researcher at Rockefeller University in New York City, discovered a hormone that seems to play a crucial role in regulating body weight. He named the hormone leptin, from the Greek word for thin, leptos.

From a practical standpoint, that’s been a connection in name only.

Researchers who thought they had the magic bullet to stifle appetite and combat overeating found that the connection between the hormone and weight gain was a bit more complicated than initially believed.

More than a decade later, the promise of leptin as the key to overcoming obesity has remained unfulfilled. Nonetheless, the discovery has opened the door to a whole new avenue of obesity research and may still prove to be the answer to weight gain. In the meantime, practical strategies aimed at using the leptin connection to lose weight remain more theory than fact.

Leptin is a hormone produced by fat tissue and secreted into the bloodstream. In essence, leptin levels give the brain a status report on the body’s fat content. The more fat, the more leptin produced.

Those leptin levels, Friedman discovered, affect the hypothalamus, a walnut-sized part of the brain that regulates appetite. As the hypothalamus senses higher levels of leptin, it acts to suppress appetite and signals other parts of the brain to increase metabolism so that more energy is expended. That burns more calories, and in theory, burns the excess fat.

If leptin levels drop, however, the hypothalamus acts in the opposite direction. Metabolism is slowed to conserve energy, and appetite is revved up to increase caloric intake. In extreme cases, low leptin levels can spur the body into a starvation survival mode, shutting down non-essential functions, including the reproductive cycle and bone development.

Friedman says that leptin may be part of a sophisticated cycle the body uses to regulate weight with tremendous precision. A typical person consumes about 10 million calories in his or her lifetime, yet the typical weight gain for men between the ages of 20 and 60 is about a half-pound per year. That means that calories consumed and calories burned must be within 0.2 percent of each other. That’s several times more accurate than any nutritionist could be in counting calories, Friedman says.

Missed signals

But when that system malfunctions, people can continue to put on the weight. Laboratory mice that lack the capacity to produce leptin become massively obese. But when Friedman injected them with synthetic leptin, the mice lost weight.

The clinical community jumped all over the leptin discovery. Biotech giant Amgen bought the rights to market synthetic leptin as an obesity cure. But clinical trials in which obese patients were given injections of leptin proved disappointing.

The researchers later discovered that the vast majority of obese people already have plenty of leptin in their bloodstream. They had become resistant to leptin, much as type 2 diabetics become resistant to insulin.

Friedman suggests that may be due to genetics. He theorized that in pre-historic days in environments where food was in limited supply, those who had a genetic predisposition to react less to leptin had an evolutionary advantage. They would be more likely to store more of their energy as fat, giving them a better chance of surviving longer periods with less food. In modern times, some people may still carry that genetic predisposition, which in the day of ample food supply causes them to become obese.

Leptin has proven effective in treating a small percentage of patients with weight issues. Friedman describes the case of a 200-pound, 9-year-old girl whose legs were so large she could barely walk. Like the mice in Friedman’s study, the girl had a genetic defect that prevented her from producing leptin on her own. Treatments with the hormone drastically reduced her caloric intake and allowed her to return to a normal weight.

Patients with a condition known as lipodystrophy lack fat cells and therefore produce little leptin. They often develop diabetes, which has also been linked to obesity. Leptin treatment has successfully reversed the insulin resistance in many of those patients.

And while the clinical trials giving synthetic leptin to patients didn’t result in weight loss for most test subjects, some did lose weight. It’s possible that those were patients who underproduce leptin, and so they lost weight when their leptin levels increased. The success with that subgroup may have been overshadowed by a larger number of leptin-resistant patients.

Applied knowledge

Some diet books have tried to build on the leptin discovery and claim to address leptin resistance. But many of those diets mirror standard nutritional advice without specifically addressing leptin resistance.

”The Rosedale Diet” by Colorado physician Ron Rosedale claims to regulate leptin through a diet high in healthy fats and low in carbohydrates, saturated fat and trans-fats, along with 15 minutes of exercise per day. ”Mastering Leptin” by nutritionist Byron J. Richards and his wife, Mary Guignon Richards, also suggest that diet can overcome leptin resistance. The authors of both books own companies that sell nutritional supplements they say will help restore leptin’s effects.

Those claims have not yet been borne out by science. No legitimate clinical study has found a way to overcome leptin resistance. None of the authors returned requests for interviews.

Dr. Leo Galland, a New York City internist who penned the ”Fat Resistance Diet,” also says his book is based on leptin research. But he acknowledges his diet plan represents what he believes science will ultimately show to be true.

”The mechanism that is emerging is the one that is the basis for the theory underlying my book, which is the role of inflammation,” he says.

Galland believes that body fat causes inflammation that in turn interferes with leptin’s role in regulating body weight.

”I think there are multiple interactions that link leptin resistance and inflammation,” he says. ”Understanding them will explain the links between obesity, diabetes and a whole bunch of related diseases.”

Galland also points out that many of the conditions associated with obesity – heart disease, diabetes, arthritis and asthma – are associated with inflammation.

There does appear to be a connection between leptin resistance and inflammation, giving credence to Galland’s theory. Researchers from the University of Pittsburgh recently investigated the link between leptin and C-reactive protein, or CRP. The protein is produced by the liver and typically increases as part of the immune system’s inflammatory response. It is considered a marker of high blood pressure and heart disease risk.

The researchers, led by Dr. Allen Zhao, used mice that had become obese because they lack the gene necessary to produce leptin. When they injected the mice with leptin, the mice lost weight. But when they injected leptin and CRP, the mice stayed fat.

”We know that CRP binds to leptin and this impairs its signaling, but we don’t know how this is so,” Zhao says. ”It may be that the coupling of the two makes crossing the blood-brain barrier difficult, or it may be that as a package it can’t bind to leptin receptors in the brain.”

CRP is also elevated in obese people, but scientists don’t know if CRP contributes to weight gain or weight gain boosts CRP. The team is now studying whether statin drugs, which can lower levels of CRP, might be a way to overcome leptin resistance.

Researchers at Harvard University found that molecules produced by the body to reduce inflammation can interfere with leptin signaling. Both of those processes could be responsible for leptin resistance. Last year, those same researchers found that asthmatics have high levels of leptin as well, a possible explanation of why so many obese people suffer from asthma.

Galland’s diet plan consists of eating foods that will minimize inflammatory response. That includes fewer processed foods, but also plenty of the fruits and vegetables rich in anti-inflammatory phytonutrients and fish rich in omega-3 fatty acids.

Scientists have known for some time that eating omega-3s from fish and other sources improves heart health. A recent study from researchers at the Mayo Clinic showed that a diet rich in fish also leads to lower levels of leptin. The researchers studied neighboring African tribes who shared a genetic history but were separated geographically and ate significantly different diets. The tribe that lived by a lake and ate mostly fish had lower levels of leptin, regardless of their weight, than the other tribe, which ate mostly fruits and vegetables.

”We speculate that a fish diet may change the relationship between leptin and body fat and somehow help make the body more sensitive to the leptin message,” says Dr. Virend Somers, a cardiologist with the Mayo Clinic and senior author of the study.”

Galland says the foods he chose as anti-inflammatories are the same foods that nutritionists recommend for a healthy diet.

”Everything that would make a diet healthy is addressed: protein, fiber, low-glycemic index, loaded with fruits and vegetables, loaded with omega-3s,” he says. ”It happens to be an excellent anti-inflammatory diet. I don’t think that’s any accident, because inflammation is the cornerstone of all these chronic diseases.”

Changing perceptions

Whether all the connections between obesity, chronic disease, inflammation and leptin prove to be significant remains to be seen. But even if the leptin discovery doesn’t provide a cure for obesity in the short term, it may help change opinions about obesity and attitudes toward overweight individuals.

In an article published in Science magazine in 2003, Friedman argued that the drive to eat is, to a large extent, hardwired, and differences in weight genetically determined.

”There can be no meaningful discussion of this subject until we resist the impulse to assign blame,” he wrote. ”Nor can we hold to the simple belief that with willpower alone, one can consciously resist the allure of food and precisely control one’s weight.”

The leptin discovery also helps to explain why maintaining weight loss is so difficult. Once the fat is lost and leptin levels drop, the body cuts back on energy expenditure. Thus the dieter must maintain a disproportionately low caloric intake to stabilize his or her new weight. But the lower levels of leptin are also boosting appetite at the same time, he wrote.

”The greater the weight loss, the greater the hunger, and sooner or later for most dieters, a primal hunger trumps the conscious desire to be thin.”

Markian Hawryluk can be reached at 617-7814 or mhawryluk@bendbulletin.com.