Distinct physiological characteristics and altered glucagon signaling in GHRH knockout mice: Implications for longevity

Abstract Our previous research has demonstrated that mice lacking functional growth hormone‐releasing hormone (GHRH) exhibit distinct physiological characteristics, including an extended lifespan, a preference for lipid utilization during rest, mild hypoglycemia, and heightened insulin sensitivity. They also show a further increase in lifespan when subjected to caloric restriction. These findings suggest a unique response to fasting, which motivated our current study on the response to glucagon, a key hormone released from the pancreas during fasting that regulates glucose levels, energy expenditure, and metabolism. Our study investigated the effects of an acute glucagon challenge on female GHRH knockout mice and revealed that they exhibit reduced glucose production, likely due to suppressed gluconeogenesis. However, these mice showed an increase in energy expenditure. We also observed alterations in pancreatic islet architecture, with smaller islets and a reduction of insulin‐producing beta cells but no changes in glucagon‐producing alpha cells. Additionally, the analysis of hepatic glucagon signaling showed a decrease in glucagon receptor expression and phosphorylated CREB. In conclusion, our findings suggest that the unique metabolic phenotype observed in these long‐lived mice may be partly explained by changes in glucagon signaling. Further exploration of this pathway may lead to new insights into the regulation of longevity in mammals.