Juli Bai, Ph.D., first author of the new paper, and Feng Liu, Ph.D., professor of pharmacology, UT Health San Antonio.
Obesity activates a specific biological pathway in obese mice, UT Health San Antonio researchers announce
Obesity does a lot more than make us hesitant to go to the beach in our swimsuits. Scientists are finding that, far from being innocent or harmless, extra weight fuels inflammation, impairs cell energy and fosters insulin resistance.
All of this can lead to diabetes.
“There are missing gaps in our understanding of this process,” said Feng Liu, Ph.D., professor of pharmacology at The University of Texas Health Science Center, now called UT Health San Antonio™.
Dr. Liu is senior author of new research—published Oct. 30 in Proceedings of the National Academy of Sciences—that at least partially explains how obesity, mitochondrial dysfunction, inflammation and insulin resistance can all be linked.
Insulin is the hormone secreted by the pancreas to control blood glucose. In type 2 diabetes, insulin-producing cells decrease in number and the available insulin isn’t used efficiently (known as insulin resistance). Obesity is well known to be a risk factor causing insulin resistance, yet the underlying mechanisms remain elusive.
Mitochondria are the energy centers in cells. Our bodies need these power plants to operate properly because all organs, especially the brain, require ATP, which is the body’s energy currency.
Pathway activated in obese mice
Obesity impairs mitochondrial function, which leads to the activation of a specific biological pathway in obese mice, the UT Health San Antonio team found. The scientists also noticed that deactivating the pathway reduces inflammation and improves insulin sensitivity, making the body more responsive to insulin.
The pathway, called cGAS-cGAMP-STING, was long known to be involved in the immune system’s response to viruses and bacteria. The pathway is activated by viral and bacterial DNA.
In recent years, scientists also found that the cGAS-cGAMP-STING pathway is activated by mitochondrial DNA. The UT Health San Antonio team hypothesized that obesity might also activate the pathway.
Confirmed in 2 mouse models of obesity
“So we tested this hypothesis in two different mouse models of obesity,” Dr. Liu said. “In both models, this pathway is activated. It showed, for the first time in the obesity-metabolism field, that activation of this pathway may play a role in obesity-induced inflammation and insulin resistance.”
This discovery provides a potential pharmacological target for intervening in the damaging effects of obesity. “This is very exciting, because it shows a mechanism that links obesity, mitochondrial dysfunction, inflammation and insulin resistance,” Dr. Liu said.
Juli Bai, Ph.D., postdoctoral fellow in Dr. Liu’s lab, is first author of the paper. The authors are from the Joe R. & Teresa Lozano Long School of Medicine at UT Health San Antonio.
The University of Texas Health Science Center at San Antonio, with missions of teaching, research and healing, is one of the country’s leading health sciences universities and is now called UT Health San Antonio™. UT Health’s schools of medicine, nursing, dentistry, health professions and graduate biomedical sciences have produced more than 33,000 alumni who are advancing their fields throughout the world. With seven campuses in San Antonio and Laredo, UT Health San Antonio has a FY 2018 revenue operating budget of $838.4 million and is the primary driver of its community’s $37 billion biomedical and health care industry. For more information on the many ways “We make lives better®,” visit www.uthscsa.edu.
Proc Natl Acad Sci U S A. 2017 Oct 30. pii: 201708744. doi: 10.1073/pnas.1708744114. [Epub ahead of print]
DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA release-activated cGAS-cGAMP-STING pathway.
Bai J1,2, Cervantes C2, Liu J2, He S2, Zhou H1, Zhang B2, Cai H2, Yin D2, Hu D2, Li Z1,2, Chen H1, Gao X3, Wang F4, O’Connor JC2,5, Xu Y6,7, Liu M1,8, Dong LQ9, Liu F10,2.
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