A drug that appears to target specific intestinal bacteria in mice may lead to new treatments for obesity and diabetes in humans.
Mice fed a high-fat diet and provided tempol, an antioxidant drug that may also help protect people from the effects of radiation, were significantly less obese than those that did not receive the drug.
“The two interesting findings are that the mice that received tempol didn’t gain as much weight and the tempol somehow impacted the gut microbiome of these mice,” says Andrew Patterson, assistant professor of molecular toxicology at Penn State.
“Eventually, we hope that this can lead to a new line of therapeutics to treat obesity and diabetes.”
The microbiome is the biological environment of microorganisms within the human body.
Tempol reduces some members of a bacteria—a genus of Lactobacillus—in the guts of mice. When the Lactobacillus levels decrease, a bile acid—tauro-beta-muricholic acid—increases. This inhibits FXR, farnesoid X receptor, which regulates the metabolism of bile acids, fats, and glucose in the body.
“The study suggests that inhibiting FXR in the intestine might be a potential target for anti-obesity drugs,” says Frank J. Gonzalez, laboratory metabolism chief of the National Cancer Institute.
Tempol may help treat type 2 diabetes symptoms. In addition to lower weight gain, the tempol-treated mice on a high-fat diet had lower blood glucose and insulin levels.
“Previously, Dr. (James) Mitchell observed a significant difference in weight gain in mice on tempol-containing diet,” Patterson says. “He approached us to help figure out what was going on, and it had been an interesting journey wading through the complexities of the microbiome.”
Mitchell is radiation biology branch chief at the National Cancer Institute.
Other studies have hinted at the relationship between tempol, the gut microbiome, and obesity, but did not focus on why the drug seemed to control weigh gain, Patterson says.
Manipulate the microbiome
These studies demonstrate how integrated the 100 trillion microbes that make up the human microbiome are with metabolism and health and how the microbiome may provide more pathways to treating other disorders.
“There is a tremendous interest in how the microbiome can be manipulated in a therapeutic way,” Patterson says. “And we need to look at these microbiome management techniques in a good, unbiased way.”
For the study published in Nature Communications, researchers dissolved tempol in drinking water, or delivered it directly to the mice. Within three weeks, tempol reduced the weight gain for the mice in that group. The mice showed significant reduction in weight gain even after 16 weeks.
To further test the role of FXR in obesity, the researchers placed mice that were genetically modified so that they lack FXR on the same high-fat diet. This group was resistant to the effects of tempol and taura-beta-muricholic acid, which further strengthened the importance of FXR in mediating the anti-obesity effect.
There are indications that FXR plays a similar role in human obesity and diabetes, Gonzalez says.
The researchers must now test the treatments to ensure it is effective in humans, and check for any potential side effects, including cancer.
The work was supported by the Center for Cancer Research, National Institutes of Health and the Pennsylvania Department of Health, using Tobacco CURE funds.
Source: Penn State