Tape measure on a fork

Why obese bodies resist leptin

MONASH (AUS) — Researchers have discovered how a key causal component of obesity—resistance to the hormone leptin—develops.

Tony Tiganis, lead author of a study published in the journal Cell Metabolism, says our bodies produce leptin in response to increasing fat deposits.

“Acting on a part of the brain called the hypothalamus, leptin instructs the body to increase energy expenditure and decrease food intake, and so helps us maintain a healthy body weight,” says Tiganis, a professor in the biochemistry and molecular biology department at Monash University.

Tony Tiganis (right) with research team member Kim Loh. (Credit: Monash University)

“The body’s response to leptin is diminished in overweight and obese individuals, giving rise to the concept of ‘leptin-resistance’. We’ve discovered more about how ‘leptin-resistance’ develops, providing new directions for research into possible treatments.”

Two proteins are already known to inhibit leptin in the brain and Tiganis’ team have discovered a third. In mice, this third protein becomes more abundant with weight-gain, exacerbating leptin-resistance and hastening progression to morbid obesity.

The study showed that the three negative regulators of leptin take effect at different stages, shedding light on how obesity progresses.

“Drugs targeting one of the negative regulators are already in clinical trials for Type 2 Diabetes, however, our research shows that in terms of increasing leptin-sensitivity in obesity, targeting only one of these won’t be enough. All three regulators might need to be switched off,” says Tiganis.

The study showed that high fat diet-induced weight gain is largely prevented in genetically modified mice when two of the negative regulators are deleted in the brain.

“We now have to determine what happens when all three negative regulators are neutralized. Do we prevent high fat diet-induced obesity?”

Tiganis says the more that is known about obesity, the better equipped scientists are to develop drugs to support good diet and exercise choices.

“Humans have a deep-seated attraction to overeating and nutrient-rich food, inherited from our hunter-gatherer ancestors. Now that food is more readily available and our lifestyles are less active, our evolutionary drive to overeat is becoming problematic.”

More than four million Australians are obese and if current trends continue, by 2020, more than 80 percent of adults and almost one third of children will be overweight or obese. Studies indicate that obesity and related health issues cost Australians more than $56 billion a year.

“Simply telling people to eat less and exercise more is not going to be sufficient to reverse the obesity trend. There is a pressing need to develop novel drugs that complement diet and exercise to both prevent and treat this disease,” says Tiganis.

More news from Monash University: www.monash.edu.au/news/