Dr Luke Wiseman of Scripps Research said: “We were able to activate this pathway in both the liver and pancreas with this one compound, and that contributed to a significant improvement in the metabolic health of fatty animals. enlarged.
Dr Enrique Saez added: “This is the first time anyone has demonstrated that a small molecule that activates this pathway has therapeutic effects in live animals.
The research is a collaboration between the laboratories of Saez and Wiseman, both professors in the Department of Molecular Medicine at Scripps Research and co-authors of this new paper.
Type 2 diabetes remains a major public health problem: an estimated 30 million people have it in the United States alone. Largely due to overweight and obesity, it deprives the body of normal blood sugar regulation and causes a myriad of health problems including a higher risk of heart disease, stroke, kidney disease, kidney damage, and more. neuropathy, retinal degeneration and some cancers. There are many medications to treat type 2 diabetes, but none of them work well for every patient.
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 XBP1, thereby altering the activity of a wide range of genes, including many metabolic genes, in an attempt to reduce cellular stress. Previous studies suggest that activity of this pathway can, at least in the short term, protect the liver and adipocytes from obesity-induced stresses.
However, the IRE1/XBP1s pathway is not a simple diabetes drug target. Previous research has shown that keeping IRE1/XBP1 in chronic on mode damages cells, induces inflammation, and exacerbates overall metabolic dysfunction.
“IRE1/XBP1s signaling is a response to cellular stress, and keeping it constant essentially tells the cell that that stress cannot be resolved,” Wiseman said.
In the new study, the researchers showed that a compound they identified several years ago, IXA4, activates IRE1/XBP1s for just a few hours at a time. Because it allows IRE1 to be turned off, it could, in principle, be given daily without causing the harmful signals seen with continuous IRE1 activation, making it a promising candidate for discovery. treatments in humans.
The team used IXA4 to treat mice that became obese due to a high-fat, high-calorie diet. After just 8 weeks, the treated mice had improved glucose metabolism and insulin activity, less fat accumulation and liver inflammation, and no loss of insulin-producing cells in the pancreas compared with the mice. untreated obese mice.
IXA4 can only reach a limited number of tissues including the liver and pancreas, and so the team is now developing other compounds that can penetrate a broader group of cells including fat cells. .
“We are also continuing to work with IXA4 as a potential treatment for other metabolic disorders such as fatty liver disease,” says Saez.
The study’s first authors were Aparajita Madhavan, PhD, then a postdoctoral fellow at the Wiseman lab, and Bernard Kok, PhD, a postdoctoral research associate at the Saez lab.
IXA4 was developed in collaboration with the lab of Jeffery Kelly, PhD, Professor of Chemistry Lita Annenberg Hazen at Scripps Research.
“Pharmacological activation of IRE1/XBP1s promotes systematic adaptive remodeling in obesity” co-authored by Aparajita Madhavan, Bernard Kok, Bibiana Rius, Julia Grandjean, Adekunle Alabi, Verena Albert, Ara Sukiasyan, Evan Powers, Andrea Galmozzi, Enrique Saez and Luke Wiseman, all of Scripps Research at the time of the study.
The work was funded by the National Institutes of Health (AG046495, DK123038, DK114785).
Source: Eurekalert
