Microbiome Influences Obesity

Researchers from the laboratories of J. Mark Brown, PhD, and Stanley Hazen, MD, both of the Department of Cellular & Molecular Medicine, discovered that blocking an intestinal microbial pathway (TMAO) can prevent obesity and insulin resistance, which are major risk factors for type II diabetes. The research, published in Cell Reports, builds on Dr. Hazen’s landmark discoveries linking gut bacteria, TMAO, and cardiovascular disease.

Since cardiovascular disease and obesity are so closely linked, the team hypothesized that TMAO may also be involved in metabolic pathways that lead to obesity. They focused on a host enzyme called flavin-containing monooxygenase 3(FMO3), which converts TMAO into its active form. They discovered that mice that had a missing or deactivated FMO3 gene were protected from obesity, even when fed a high-fat, high-calorie diet. Furthermore, the FMO3-negative mice showed higher expression of genes associated with beige or brown fat cells, which are more metabolically active than white fat cells.

The study confirmed in 435 patients that high levels of TMAO are associated with higher incidence of Type 2 diabetes.

 “Obesity, diabetes and cardiovascular disease are strongly linked. While the microbiome has been shown to affect cardiovascular disease, there is as yet no concrete evidence of precisely how gut bacteria influence obesity,” Brown said. “These findings shed light on a possible way to manipulate the microbiome with therapeutics to combat our obesity and diabetes epidemic.”

Rebecca Schugar, PhD, of the Brown lab, is first author on the publication.

“Given the numerous strong associations of the gut microbe-driven TMAO pathway with human disease, this work has broad implications for drug discovery efforts targeting gut microbes themselves,” said Dr. Hazen, whoholds the Jan Bleeksma Chair in Vascular Cell Biology and Atherosclerosis.