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Obesity prevented in mice treated with gene-disabling nanoparticles

Strategy uses particles to target gene in specific immune cells

by Jim DrydenMay 1, 2020

Teitelbaum lab

Disabling a gene in specific mouse cells, researchers at Washington University School of Medicine in St. Louis have prevented mice from becoming obese, even after the animals had been fed a high-fat diet.

The researchers blocked the activity of a gene in immune cells. Because these immune cells — called macrophages — are key inflammatory cells and because obesity is associated with chronic low-grade inflammation, the researchers believe that reducing inflammation may help regulate weight gain and obesity.

The study is published May 1 in The Journal of Clinical Investigation.

“We’ve developed a proof of concept here that you can regulate weight gain by modulating the activity of these inflammatory cells,” said principal investigator Steven L. Teitelbaum, MD, the Wilma and Roswell Messing Professor of Pathology & Immunology. “It might work in a number of ways, but we believe it may be possible to control obesity and the complications of obesity by better regulating inflammation.”

When people are obese, they burn fewer calories than those who are not obese. The same is true for mice. But according to co-first author Wei Zou, MD, PhD, an assistant professor of pathology & immunology, the researchers found that obese mice maintained the same level of calorie burning as mice that were not obese — after the research team deleted the ASXL2 gene in the macrophages of the obese mice and, in a second set of experiments, after they injected the animals with nanoparticles that interfere with the gene’s activity.

Despite high-fat diets, the treated animals burned 45% more calories than their obese littermates with a functioning gene in macrophages.

Exactly why this prevented obesity in the mice isn’t clear. Co-first author Nidhi Rohatgi, PhD, an instructor in pathology, said it appears to involve getting white fat cells — which store the fat that makes us obese — to behave more like brown fat cells — which help to burn stored fat. The strategy is a long way from becoming a therapy, but it has the potential to help obese people burn fat at rates similar to rates seen in lean people.

“A large percentage of Americans now have fatty livers, and one reason is that their fat depots cannot take up the fat they eat, so it has to go someplace else,” Teitelbaum said. “These mice consumed high-fat diets, but they didn’t get fatty livers. They don’t get type 2 diabetes. It seems that limiting the inflammatory effects of their macrophages allows them to burn more fat, which keeps them leaner and healthier.”

Zou W, et al. Myeloid-specific Axsl2 deletion limits diet-induced obesity by regulating energy expenditure. The Journal of Clinical Investigation, May 1, 2020.

This work was supported by the National Heart, Lung and Blood Institute; the National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute of Allergy and Infectious Diseases and the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health (NIH). Grant numbers HL1388163, AR064755, AR068972, AR070975, HL38180, DK56260, P30 DK52574, P41 EB025815, HL073646, DK102691, AI019653, DK109668, DK056341, AR046523, DK111389 and P30 AR074992. Additional funding from the Physician-Scientist Training Program at Washington University School of Medicine and the Children’s Discovery Institute.

Washington University School of Medicine’s 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Jim retired from WashU Medicine Marketing & Communications in 2023. While at WashU Medicine, Jim covered psychiatry and neuroscience, pain and opioid research, orthopedics, diabetes, obesity, nutrition and aging. He formerly worked at KWMU (now St. Louis Public Radio) as a reporter and anchor, and his stories from the Midwest also were broadcast on NPR. Jim hosted the School of Medicine's Show Me the Science podcast, which highlights the outstanding research, education and clinical care underway at the School of Medicine. He has a bachelor's degree in English literature from the University of Missouri-St. Louis.