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UC Davis researchers target obesity-related illnesses

Newly published research in the Proceedings of the National Academy of Sciences indicates that a drug discovered and developed in the laboratory of Bruce Hammock of the UC Davis department of entomology and nematology may have a major role in preventing and treating illnesses associated with obesity.

More than 43 percent of adults in the United States are obese, according to the Center for Disease Control and Prevention. Obesity increases the risk of coronary artery disease, stroke, type 2 diabetes and certain kinds of cancer.

The drug, a soluble epoxide hydrolase (sEH) inhibitor, appears to regulate “obesity-induced intestinal barrier dysfunction and bacterial translocation,” the 12-member team of researchers from UCD, University of Massachusetts and University of Michigan discovered. The same non-opioid drug is being investigated in human clinical safety trials in Texas to see if it blocks chronic pain associated with diseases such as spinal cord injury, diabetes and inflammatory bowel disease.

365体育投注The research, funded by multiple federal grants, is titled “Soluble Epoxide Hydrolase Is an Endogenous Regulator of Obesity-Induced Intestinal Barrier Dysfunction and Bacterial Translocation.”

The promising new drug was discovered and developed in the laboratory of Bruce Hammock of the UC Davis department of entomology and nematology.
Courtesy photo

“Obesity usually causes the loss of tight junctions and leaky gut,” said first author Yuxin Wang, a postdoctoral researcher who joined the Hammock lab in 2019 from the department of food sciences at the University of Massachusetts, Amherst. “In normal conditions, the gut mucosal barrier is like a defender to protect us from the ‘dirty things’ in the lumen, such as bacteria and endotoxin. For obese individuals, the defender loses some function and leads to more ‘bad things’ going into the circulation system, causing systemic or other organ disorders.”

365体育投注Although intestinal dysfunction and other problems enhancing bacterial translocation underlies many human diseases, “the mechanisms remain largely unknown,” said Wang, who holds a doctorate in biochemistry and molecular biology from the Chinese Academy of Sciences. “What we found is sEH inhibition can repair the defender function (barrier function), decrease the ‘bad things’ going into the blood (bacteria translocation) and reduce inflammation of fat.”

365体育投注“Our research shows that sEH is a novel endogenous regulator of obesity-induced intestinal barrier dysfunction and bacterial translocation,” said corresponding author Guodong Zhang, a former researcher in the Hammock lab and now with the food science department and molecular and cellular biology graduate program at the University of Massachusetts.

365体育投注“To date, the underlying mechanisms for obesity-induced intestinal barrier dysfunction remain poorly understood. Therefore, our finding provides a novel conceptual approach to target barrier dysfunction and its resulting disorders with clinical/transitional importance.

“Furthermore,” Zhang said, “in this research, we showed that the effects of sEH are mediated by gut microbiota-dependent mechanisms. These research efforts could help to bridge two disparate fields, lipid signaling autacoids and gut microbiota, and hold great promise for success to create an important new research area.”

Corresponding author Hammock, a distinguished UC Davis professor who holds a joint appointment with the department of entomology and nematology and the Comprehensive Cancer Center, praised Zhang’s “amazing record while he was a postgraduate at UC Davis, and now in food science department at the University of Massachusetts, where he recently received tenure.”

Zhang mentored two co-authors of the paper: Yuxin and Weicang Wang, both formerly of the Massachusetts food science department  and now with the Hammock lab.

“I feel so lucky that Yuxin and Weicang have joined my laboratory,” Hammock said. “The drugs studied in this PNAS paper are now in human clinical trials and on a path to replace opioid analgesics for pain treatment. I hope the continuing work of Guodong, Weicang and Yuxin will evaluate them as treatments for a variety of inflammatory bowel diseases.”

365体育投注Andreas Baumler, professor and vice-chair of research in the UCD department of medical microbiology and immunology, who was not affiliated with the study, said: “Obesity-induced gut leakage and bacterial translocation can be ameliorated by targeting microbes with antibiotics, suggesting that the microbiota contributes to disease. However, the work by Zhang and co-workers suggest that rather than targeting the microbes themselves, obesity-induced gut leakage and bacterial translocation can be normalized by silencing a host enzyme, which identifies host metabolism as an alternative therapeutic target.”

365体育投注In addition to Hammock, Zhang, Yuxin and her husband Weicang, the other eight co-authors on the team are: Jun Yang, Sung Hee Hwang and Debin Wan of the Hammock lab, UCD department of entomology and nematology, and UC Davis Comprehensive Cancer Center; Kin Sing Stephen Lee, formerly of the Hammock lab, and Maris Cinelli, both of the department of pharmacology and toxicology, Michigan State University, Lansing; Katherine Sanidad and Hang Xiao, department of food science and the molecular and cellular biology graduate program, University of Massachusetts, Amherst; and Daeyoung Kim, department of mathematics and statistics, University of Massachusetts, Amherst.

The research was funded by grants from the National Institute of Food and Agriculture, U.S. Department of Food and Agriculture (USDA); National Cancer Institute; USDA Hatch Grant; National Institute of Environmental Health Sciences Superfund Research Program; and National Science Foundation.

According to the CDC, many obesity-related conditions that lead to diseases are preventable. In 2008, the estimated annual medical cost of obesity in the United States tallied $147 billion. The medical cost for obese individuals averaged $1,429 higher than those of normal-weight individuals.

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