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Researchers at Scripps Research show that an experimental drug candidate called IXA4 activates a natural signaling pathway that protects mice from harmful, obesity-driven metabolic changes that could lead to diabetes.

Their findings, which they hope will translate to humans, are published in the journal Nature Communications.

“In obesity, signaling through the IRE1 arm of the unfolded protein response exerts both protective and harmful effects,” the researchers wrote. “Overexpression of the IRE1-regulated transcription factor XBP1s in liver or fat protects against obesity-linked metabolic deterioration.”

“We were able to activate this pathway in both the liver and the pancreas with this one compound, and that added up to a significant overall improvement in metabolic health of obese animals,” explained Luke Wiseman, PhD, a professor in the department of molecular medicine at Scripps Research and co-senior author on the new paper.

“This is the first time anyone has shown that a small molecule activating this pathway in this manner works to treat disease in a live animal,” added Enrique Saez, PhD, who is also a professor in the department of molecular medicine at Scripps Research and co-senior author.

For several years, Wiseman’s lab has been studying a signaling pathway involving two proteins called IRE1 and XBP1s. When activated by a certain type of cellular stress, IRE1 activates XBP1s, which in turn alters the activity of a host of genes, including many metabolic genes, in an effort to reduce cellular stress. Prior studies suggest that the activity of this pathway, at least in the short term, can protect liver and fat cells from stresses caused by obesity—stresses that can harm these cells in ways that promote diabetes.

The IRE1/XBP1s pathway is not a straightforward diabetes drug target, however. Past research has shown that keeping IRE1/XBP1 switched on chronically ends up harming cells, triggering inflammation, and worsening overall metabolic dysfunction.

“IRE1/XBP1s signaling is a response to cellular stress, and keeping it on all the time essentially tells the cell that the stress can’t be resolved—so the cell in effect kills itself,” Wiseman said.

In the new study, the researchers showed that a compound they identified a few years ago, IXA4, activates IRE1/XBP1s for just a few hours at a time.

The scientists used IXA4 to treat mice that were obese from a high-fat, high-calorie diet. After just eight weeks, the treated mice had improved glucose metabolism and insulin activity, less fat buildup and inflammation in the liver, and no loss of insulin-producing cells in the pancreas, compared to untreated obese mice.

“We’re also continuing to work with IXA4 as a potential treatment for other metabolic disorders such as fatty liver disease,” Saez said.

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