Obesity, insulin resistance and metabolic syndrome are associated with changes to the gut microbiota; however, the mechanism by which modifications to the gut microbiota lead to those disorders had been unknown – until recently.
In the study “Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome,” published in the journal Nature, researchers from Yale University reported that they have found the mechanism that alters gut microbiota and leads to obesity.
In a previous study, Gerald I. Shulman, the university’s George R. Cowgill Professor of Medicine, discovered that acetate, a short-chain fatty acid, encouraged the secretion of insulin in rodents.
To better understand the role of acetate, researchers conducted new experiments in rodent models of obesity, and compared acetate to other short-chain fatty acids.
The team found that rodents under a high-fat diet had higher levels of acetate. Researchers also found that acetate infusions stimulated the secretion of insulin by pancreatic beta cells, but the reason behind this mechanism was unclear. They also reported that when acetate was directly injected into the brain, it prompted an increase in insulin levels by triggering the parasympathetic nervous system.
“Acetate stimulates beta cells to secrete more insulin in response to glucose through a centrally mediated mechanism,” Shulman said in a recent news release. “It also stimulates secretion of the hormones gastrin and ghrelin, which lead to increased food intake.”
Researchers then aimed to determine a causal association between the gut microbiota and increased levels of insulin. The team transferred fecal matter from one set of rodents to another, and found identical alteration in insulin, levels of acetate and gut microbiota. The findings revealed that increased acetate production resulting from a nutrient–gut microbiota interaction and subsequent parasympathetic activation, could be possible therapeutic targets for obesity.
“Taken together these experiments demonstrate a causal link between alterations in the gut microbiota in response to changes in the diet and increased acetate production,” said Shulman.
The increased acetate levels then lead to increased food intake, setting off a positive feedback loop that drives obesity and insulin resistance, he explained.
Researchers now suspect that the response loop may have played a critical role in evolution, by inciting animals to fatten up when they stumbled on food high in calories during times of food shortages.
Shulman concluded: “Alterations in the gut microbiota are associated with obesity and the metabolic syndrome in both humans and rodents. In this study we provide a novel mechanism to explain this biological phenomenon in rodents, and we are now examining whether this mechanism translates to humans.”