Gut–brain axis linked again to obesity in Yale study

The findings, which appear in Nature​, showed increased acetate production caused increased food intake in rodents, setting in motion a positive feedback loop that drives obesity and insulin resistance.

If this mechanism translates to humans, there is the possibility of a therapeutic target for weight management.

By conducting a number of experiments in animal models of obesity, the team found higher levels of acetate in animals that consumed a high-fat diet. 

Increased acetate production, thought to be caused by an altered gut microbiota, specifically activated the parasympathetic nervous system.

This in turn, increased glucose-stimulated insulin secretion, excessive eating and eventually obesity. An increased level of ghrelin, a hormone that stimulates increase in appetite, was also noted.

Evolutionary process​

The study authors suggested this positive feedback loop may have served an important role in evolution, by prompting animals to fatten up when they stumbled across calorie-dense food in times of food scarcity.

However in the setting of chronic exposure to calorie-dense, abundant food, this gut microbiota–brain axis promotes obesity and other related conditions such as hyperlipidaemia, fatty liver disease and insulin resistance.

The findings build on earlier work done by the study’s lead author Dr Gerald Shulman, professor of medicine at Yale University.

Here, he observed that acetate, a short-chain fatty acid (SCFA), stimulated the secretion of insulin in rodents.

"Acetate stimulates beta cells to secrete more insulin in response to glucose through a centrally mediated mechanism,"​ said Dr Shulman. "It also stimulates secretion of the hormones gastrin and ghrelin, which lead to increased food intake."​

"Alterations in the gut microbiota are associated with obesity and the metabolic syndrome in both humans and rodents,"​ he added.

A unique environment​

Other studies have established that both increases​​ and decreases​​ in plasma and faecal SCFA concentrations can be associated with overfeeding, obesity and the metabolic syndrome.

The study did note that while the findings strongly suggest that the gut microbiota was responsible for generating increased acetate turnover and driving obesity in the rats, they could not rule out the possibility that the microbiota also controlled acetate absorption.

Energy metabolism in the colon is unique in that gut bacteria may use SCFAs, as a primary energy source, whereas most other tissues in the body use glucose.

Source: Nature ​

Published online ahead of print, 

“Acetate mediates a microbiome–brain–β- cell axis to promote metabolic syndrome.”​

Authors: Gerald Shulman et al.