How Obesity Works

Once you know how something works, it’s easier to fix it. In the fight against obesity, understanding how the disease progresses will help beat it. Researchers from Monash University made another step toward understanding obesity works by unraveling how leptin-resistance develops. 

"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," said Lead author Professor Tony Tiganis, of the Monash Obesity and Diabetes Institute and Monash University's Department of Biochemistry and Molecular Biology. "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—PTP1B and SOCS3 — are already known to inhibit leptin in the brain. This study identified a third: TCPTP. In mice, TCPTP  becomes more abundant with weight gain, exacerbating leptin-resistance and hastening progression to obesity. The study, published in Cell Metabolism, showed that the three negative regulators of leptin take effect at different stages, shedding light on how obesity progresses. elevated TCPTP to the development of cellular leptin resistance in obesity

"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," said 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 neutralised. Do we prevent high fat diet-induced obesity?"