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Most adult body fat consists of white fat cells that store excess calories, but babies are born with stores of brown and beige fat that burn energy to generate heat. Brown fat levels decrease with age, but scientists have long sought to change that, looking for ways to convert white fat cells into calorie-consuming beige fat with the goal of treating obesity and metabolic disease such as diabetes.

Now, researchers at Keio University in Japan, the ӳ����ý, and City of Hope have discovered that a low-protein diet paired with just the right mix of gut bacteria can lead to this transformation in mice. Their new study in shows how four strains of bacteria, when they sense low protein in the mouse gut, produce molecular signals that trigger white fat cells to become more beige by taking on brown fat characteristics.

“This work underscores how our gut microbiome is actively interpreting what we eat and translating it into signals the body responds to,” said study co-senior author Ramnik Xavier, a ӳ����ý core institute member, the Kurt J. Isselbacher Professor of Medicine at Harvard Medical School, and director of the Center for Computational and Integrative Biology and core member in the Department of Molecular Biology at Massachusetts General Hospital.

The scientists caution that the findings shouldn’t be directly applied in humans. The diet they studied is lower in protein than is advised for people, and previous attempts to simply give people specific bacterial strains as probiotics have largely failed. Instead, the team says a better understanding of how these bacteria work could one day allow researchers to develop medicines that mimic their effects.

“In the future, we potentially could modulate brown fat through drugs that directly impact these same molecular pathways that the microbiota are activating,” said Kenya Honda, co-senior author, professor at Keio University School of Medicine, and a visiting scholar at City of Hope, a US cancer research and treatment organization.

 
Bug hunt

The research began when Honda’s team noticed that mice consuming just a 7 percent protein diet showed increases in beige fat levels, but this diet didn’t have any effect on fat in mice with no gut bacteria.

“This suggested to us that there was something key in the gut microbiome that was responsible for converting white fat to beige fat in these low-protein conditions,” said co-first author Takeshi Tanoue of Keio University and City of Hope.

To identify which bacteria might be involved, the researchers recruited 25 healthy adults and scanned them for active beige fat; only four people had detectable levels (Honda tested himself and was disappointed to learn he wasn’t one of those four.).

The team isolated gut bacteria from the four volunteers with beige fat and transplanted the microbes into germ-free mice that were fed the low-protein diet. Animals that received bacteria from two of the four individuals began to convert white fat into beige fat. By removing one strain at a time from these mice, the researchers pinpointed four bacterial strains that were essential for this conversion and shared between the two human donors: Adlercreutzia equolifaciens, a Eubacteriaceae species, Bilophila sp., and Romboutsia timonensis.

Mice that received the four strains along with the low-protein diet had increased beige fat, better glucose tolerance, reduced weight gain, and lower cholesterol levels.

Linking bacteria to brown fat

In collaboration with Xavier’s team at the ӳ����ý, the researchers homed in on the molecules produced by each of the four strains of bacteria. The bacteria, they found, produce signals that alter the gut’s bile acids in low-protein conditions. These altered bile acids travel through the bloodstream to fat tissue, where they activate stem cells to become beige fat.

At the same time, two of the bacteria begin to make ammonia when they sense a shortage of protein. This ammonia travels to the liver, triggering production of the hormone FGF21, which increases nerve connections to fat tissue.

When the research teams blocked either the modified bile acids or the hormone, mice no longer produced brown fat when they ate a low-protein diet, demonstrating that both pathways are essential.

“What these findings tell us is that the microbiome is incredibly important in fine-tuning things like how our body stores fat,” said Xavier. “This opens up an opportunity to think about the interactions between microbes, metabolites, and metabolic disease, understand the mechanisms, and potentially translate that into interventions for metabolic health.”

The Keio University researchers are now working to understand how bacteria sense low-protein conditions in the first place, and whether drugs targeting bile acid modifications or the FGF21 hormone could influence beige fat levels in humans.

The other co-first authors of the study are Manabu Nagayama and Ayumi Roochana of Keio University, and Samuel Zimmerman of the ӳ����ý.