Scientists discover metabolites that shape risk of obesity and type 2 diabetes

Researchers have discovered metabolites that impact liver metabolism and insulin sensitivity. They travel from the intestine to the liver and then to the heart, from where they are spread to the rest of the body.

The publication in Cell Metabolism suggests that this finding may have potential applications in future treatments for obesity and type 2 diabetes.

“The hepatic portal vein drains much of the blood from the intestine to the liver. Therefore, it’s the first place to receive products from the gut microbiome. In the liver, they can be conjugated, transformed, or eliminated, and then enter the systemic circulation,” explains study first author Vitor Rosetto Muñoz, postdoctoral researcher at the Ribeirão Preto School of Physical Education and Sports at the University of São Paulo in Brazil.

“By analyzing the blood leaving the intestine and the peripheral blood circulating throughout the body, we were able to more accurately observe the enrichment of these metabolites derived from the gut microbiome in each location and, consequently, how they can modify hepatic metabolism and metabolic health.”

Zooming into metabolite differences

The study points out the recent acknowledgment of the gut microbiome as a central player in mediating interactions between genes and the environment, contributing to metabolic diseases. 

Metabolites in peripheral blood and hepatic portal vein with different genetic histories of susceptibility to metabolic diseases after receiving a high-fat diet (Image credit: Muñoz).Researchers have found differences in the gut microbiomes of humans and rodents with and without obesity, type 2 diabetes, glucose intolerance, and insulin resistance. 

However, the study notes that it is a challenge to know how this difference is created.

The new study analyzed metabolites from the blood of those who were susceptible to obesity or diabetes. The researchers collected blood connecting the intestine to the liver (hepatic portal vein) and blood traveling from the liver to the heart to the rest of the body (peripheral blood). 

“Normally, studies tend to look at metabolites present in fecal material or peripheral blood, but they don’t accurately reflect what’s first reaching the tissue of the liver, which is an important metabolic organ linked to different diseases,” says Muñoz.

Environmental and genetic factors

The team found 111 metabolites in the hepatic portal vein and 74 in peripheral blood in healthy mice. 

In mice susceptible to obesity and type 2 diabetes, exposed to a fatty diet, metabolites in the hepatic portal vein decreased to 48. The researchers explain that this shows how environmental factors can play a regulatory role.

Furthermore, genetics also play an essential role, as the researchers noticed metabolite profiles in the hepatic portal vein differed for each mouse.

“This shows that both the environment and the host’s genetics can interact in complex ways with the gut microbiome,” says Muñoz.

“As a result of these interactions, different combinations of metabolites may be sent to the liver and subsequently to the peripheral circulation. These metabolites likely play an important role in mediating the conditions that lead to obesity, diabetes, and metabolic syndrome.”

Identifying bacteria and metabolites

Researchers treated mice with antibiotics to understand which bacteria and their byproducts lead to the production of these metabolites.

They found the treatment increased metabolites such as mesaconate — linked to the metabolic pathway for energy production in cells.

The researchers then used mesaconate to treat liver cells, which improved insulin signaling and regulated genes involved in hepatic fat accumulation and fatty acid oxidation. These are known to be important for healthy metabolism.

“The metabolites found in the blood of these two sites, therefore, play important roles in mediating the effects of the microbiome on liver metabolism and the pathogenesis of type 2 diabetes and insulin resistance, which is related to eating a high-fat diet,” concludes Muñoz.

The research was conducted at Harvard Medical School in the US.