Researchers at the Tohoku University Graduate School of Medicine have uncovered a key primary step in the hepatic ERK pathway that leads to increased insulin production. While their previous work focused on aspects of the signaling pathway from the liver to the pancreas, this current study shows an even earlier step that begins in the colon when it is inflamed - triggered by obesity. The present study revealed a novel role the gastrointestinal tract plays in regulating glucose homeostasis.

Insulin is a hormone produced by β-cells in the pancreas. You can think of insulin like a key that unlocks cells to let glucose enter from the blood, so it can be used as energy. However, individuals with obesity can become insulin resistant, which causes the pancreas to secrete more insulin to try to keep up. This occurs through an inter-organ neuronal signal relay originating in the hepatic ERK pathway. Due to the close relationship between obesity and the onset of diabetes, understanding this pathway in depth could help develop new ways to treat or prevent this condition.

"The goal of this study was to define how obesity in particular triggers this cascade," says Junta Imai (Tohoku University). "We theorized that it had to do with inflammation in the colon, since pro-inflammatory factors can play an excitatory role in the hepatic ERK pathway."

The researchers developed a thorough series of experiments to determine if colonic inflammation due to obesity could impact the hepatic ERK pathway. First, the research group analyzed mice without obesity that had been given a drug to cause inflammation in the colon. As a result, they found that simply causing inflammation in the colon activates the ERK pathway in the liver, stimulates the neuronal relay pathway, and increases the number of β-cells even in the mice without obesity. Next, by analyzing colons of mice in which obesity was induced by a high-calorie diet, it was found that colonic inflammation, along with both hepatic ERK pathway activation and increased β-cells, had occurred in these obese mice.

"An exciting finding was when we tried to treat the obese mice with colon inflammation by lowering their inflammation, it actually stopped the ERK pathway in the liver from activating," explains Imai. "Despite the fact the mouse was still obese, targeting colon inflammation was exactly what was needed to alter the ERK pathway."

This research unveils a missing link in the pathway, determining that the liver senses the state of obesity through colonic inflammation, and colonic inflammation serves as the first trigger of β-cell proliferation during obesity development. These achievements will lead to advancements in understanding the mechanism behind β-cells proliferation in order to maintain normal blood glucose levels. In addition, it is anticipated that this research may help progress the development of treatments and prevention methods for diabetes.

These findings were published in JCI Insight on May 8, 2025.

This research was supported by the Japan Society of the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Scientific Research (23K24383, 22K19303, 20H05694); the Japan Science and Technology Agency (JST), Moonshot R&D (JPMJMS2023); and the Japan Agency for Medical Research and Development (AMED), AMED-PRIME (21gm6210002h0004).