Adrenal hormones in the maintenance of glucose homeostasis during prolonged fasting in male glucagon‐deficient mice

AIMS/INTRODUCTION: Glucagon is a key regulator of fasting glucose homeostasis, but the contribution of adrenal hormones during prolonged fasting remains unclear. We investigated the complementary roles of glucagon and adrenal hormones in hepatic glucose metabolism during prolonged fasting. MATERIALS AND METHODS: Male proglucagon-deficient (GCGKO) mice and adrenalectomized (ADX) mice were studied after a 36-h fast. Metabolic parameters, hepatic glycogen and lipid contents, gene expression, and liver metabolomic profiles were analyzed. RESULTS: GCGKO mice exhibited markedly elevated plasma corticosterone levels and only mildly reduced blood glucose levels despite preserved hepatic glycogen stores after a 36-h fast. Hepatic triglyceride and free fatty acid contents were significantly lower in GCGKO mice. Fasting increased the expression of genes involved in amino acid metabolism and the urea cycle in both control and GCGKO mice, but the magnitude of the response was attenuated in GCGKO mice. Hepatic amino acid levels were broadly reduced in control mice but largely preserved in GCGKO mice. In contrast, adrenalectomy in GCGKO mice resulted in severe hypoglycemia accompanied by reduced adipose tissue lipolysis and impaired hormone-sensitive lipase phosphorylation. Adrenalectomy had minimal effects on blood glucose and hepatic metabolic responses in control mice. CONCLUSIONS: Glucagon-dependent glycogen utilization, adrenal hormone-dependent adipose lipolysis, and cooperative regulation of hepatic amino acid metabolism by glucagon and adrenal hormones contribute to the maintenance of blood glucose during prolonged fasting. Adrenal hormones provide an important compensatory mechanism that preserves glucose homeostasis when glucagon signaling is impaired.