Scientists from the Tohoku University Graduate School of Medicine have identified a crucial initial mechanism in the hepatic ERK signaling pathway responsible for boosting insulin secretion. In their earlier investigations, they examined the signaling processes extending from the liver to the pancreas, but this latest research highlights an upstream event originating in the colon during inflammation—a condition prompted by obesity. The findings demonstrate a previously unrecognized function of the gastrointestinal system in maintaining glucose balance.
β-cells in the pancreas produce insulin, a vital hormone that functions much like a key, allowing glucose from the bloodstream to enter cells for energy utilization. In people affected by obesity, insulin resistance often develops, compelling the pancreas to ramp up insulin output in an effort to compensate. This compensatory response is mediated by an inter-organ neuronal signaling chain that starts in the hepatic ERK pathway. Given the strong association between obesity and diabetes development, a deeper comprehension of this pathway holds significant potential for devising innovative strategies to treat or avert the disease.
Junta Imai from Tohoku University explains, “Our objective in this study was to pinpoint precisely how obesity initiates this signaling cascade.” He adds, “We hypothesized that colonic inflammation was involved, as pro-inflammatory agents are known to stimulate the hepatic ERK pathway.”
To test this hypothesis, the research team conducted an extensive array of experiments examining the effects of obesity-induced colonic inflammation on the hepatic ERK pathway. Initially, they induced inflammation in the colons of lean mice using a specific pharmacological agent. The results were striking: this isolated colonic inflammation alone was sufficient to activate the ERK pathway in the liver, trigger the neuronal relay to the pancreas, and promote an increase in β-cell numbers, even without any obesity present in these animals.
Building on this, the scientists then scrutinized the colons of mice that had become obese through prolonged exposure to a high-calorie diet. In these models, they observed clear evidence of colonic inflammation accompanied by activation of the hepatic ERK pathway and a corresponding expansion of β-cells.
One particularly noteworthy discovery emerged when the team intervened to reduce inflammation in the colons of the obese mice. As Imai notes, “Remarkably, alleviating the colonic inflammation halted the activation of the ERK pathway in the liver entirely.” This occurred even though the mice remained obese, underscoring that targeting inflammation in the colon was the key factor in modulating the pathway’s activity.
Overall, this study bridges a critical gap in our understanding of the pathway, establishing that the liver detects obesity primarily through signals from inflamed colonic tissue. Colonic inflammation thus emerges as the primary initiator of β-cell proliferation as obesity takes hold. These insights promise to advance our knowledge of the processes driving β-cell expansion to sustain stable blood glucose levels. Furthermore, they pave the way for novel therapeutic and preventive approaches against diabetes by focusing on gastrointestinal inflammation.
The research appeared in JCI Insight on May 8, 2025.
Funding for this work came from the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Scientific Research (grants 23K24383, 22K19303, 20H05694), the Japan Science and Technology Agency (JST) Moonshot R&D program (JPMJMS2023), and the Japan Agency for Medical Research and Development (AMED) AMED-PRIME initiative (21gm6210002h0004).
