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Sensor Protein Tells Cells to Burn Fat

The discovery of a “sensor” protein that instructs cells to burn their fat stores could play a major role in the fight against obesity and metabolic diseases such as type 2 diabetes.

The NLRP1 protein is switched on when increased dietary intake triggers cells to become unstable. Activating the protein sets off a chain of events that instructs cells to use up their energy or fat stores to prevent excess fat from accumulating. “We showed that without NLRP1, fat stores continue to build up, especially with a high-energy diet, leading to obesity,” said Dr Seth Masters from the Walter and Eliza Hall Institute.

NLRP1 is more commonly known for its role in the immune system. “However, it is becoming increasingly clear that immune signalling proteins also have an important role in regulating metabolism,” Masters said.

“This study provides compelling evidence that the immune system is activated not only during infection, but also in response to the loss of metabolic equilibrium associated with a high-energy diet,” said

Dr Andrew Murphy of the Baker IDI Heart and Diabetes Institute. “In order to combat the worldwide obesity epidemic it is essential to understand the immune mechanisms the body uses to prevent obesity, insulin resistance and the development of type 2 diabetes.”

The key to NLRP1 and its anti-obesity effects is how it controls an important lipid-regulating hormone called interleukin-18 (IL-18). “We showed for the first time that NLRP1 is the key to IL-18 production, explaining how it acts to reduce obesity,” Murphy said.

“Our long-term goal would be to develop a small molecule that activates the pathway to produce IL-18. In people who are obese, this would help the body to switch on this system and burn existing fat stores.”

However, the investigators cautioned that the treatment would have to be tightly controlled to avoid potential side-effects. “Our research showed that activation of NLRP1 could be exacerbated by some diets, and identified that there is a fine balance between increasing the cell’s fat-burning abilities and causing harm,” Masters warned.

“This shows us just how active the pathway is, which is important if you are looking at it in a therapeutic sense. It suggests that treatment would be most safe if given in small doses over a long period of time, which is less likely to have potentially negative consequences.”

The research has been published in Cell Metabolism.