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

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.

Insights into the Role of Glucagon Receptor Signaling in Metabolic Regulation from Pharmacological Inhibition and Tissue-Specific Knockout Models.

While glucagon has long been recognized as the primary counter hormone to insulin's actions, it has recently gained recognition as a metabolic regulator with its effects extending beyond control of glycemia. Recently developed models of tissue-specific glucagon receptor knockouts have advanced our understanding of this hormone, providing novel insight into the role it plays within organs as well as its systemic effects. Studies where the pharmacological blockade of the glucagon receptor has been employed have proved similarly valuable in the study of organ-specific and systemic roles of glucagon signaling. Studies carried out employing these tools demonstrate that glucagon indeed plays a role in regulating glycemia, but also in amino acid and lipid metabolism, systemic endocrine, and paracrine function, and in the response to cardiovascular injury. Here, we briefly review recent progress in our understanding of glucagon's role made through inhibition of glucagon receptor signaling utilizing glucagon receptor antagonists and tissue specific genetic knockout models.