Editors' ChoiceMetabolism

Same Hormone, Different Actions

Sci. Signal.  02 Jul 2013:
Vol. 6, Issue 282, pp. ec147
DOI: 10.1126/scisignal.2004469

Glucagon released by pancreatic alpha cells increases hepatic glucose production by activating its receptor, a G protein–coupled receptor (GPCR) that stimulates protein kinase A (PKA), in the liver. Under normal conditions, this increase in hepatic glucose production is not sustained, even if plasma glucagon is artificially maintained at a high concentration. However, chronic hyperglucagonemia promotes hyperglycemia under diabetic conditions. Because glucagon binds to sites in the hypothalamus, Mighiu et al. (see also Edgerton and Cherrington) investigated the role of the hypothalamus in glucagon action. Glucagon receptors were detectable in the mediobasal hypothalamus (MBH) by immunoblotting and immunohistochemistry. Administration of glucagon into the MBH of rats increased the glucose infusion rate (a measure of glucose uptake by tissues) and decreased hepatic glucose production under euglycemic clamp conditions, which measures insulin sensitivity, and improved glucose tolerance under nonclamp conditions. The ability of glucagon administration into the MBH to increase the glucose infusion rate and decrease hepatic glucose production was attenuated by infusing the MBH with an antibody directed against the glucagon receptor or a glucagon receptor antagonist. Suppression of hepatic glucose production by glucagon infused into the MBH required PKA activity in the MBH and hepatic vagal innervation. When insulin and glucose concentrations were held steady, intravenous glucagon injection to cause central hyperglucagonemia transiently increased hepatic glucose production, an increase that was sustained when the glucagon receptor antagonist was infused into the MBH. When the glucagon receptor antagonist or PKA inhibitor was infused into the MBH, intravenous glucagon injection triggered a greater increase in plasma glucose concentrations and did not increase PKA activity in the MBH compared to the response of animals infused with saline. Furthermore, intravenous glucagon injection into rats on a high-fat diet increased plasma glucose concentrations to a greater extent than rats on a normal diet, and infusion of glucagon into the MBH of these rats under euglycemic clamp conditions failed to increase the glucose infusion rate, decrease hepatic glucose production, or activate PKA in the MBH. Whereas glucagon binding to receptors in the liver increases hepatic glucose production, glucagon binding to receptors in the hypothalamus acts to limit the increase in hepatic glucose production, a signaling pathway that may be disrupted by a high-fat diet.

P. I. Mighiu, J. T. Y. Yue, B. M. Filippi, M. A. Abraham, M. Chari, C. K. L. Lam, C. S. Yang, N. R. Christian, M. J. Charron, T. K. T. Lam, Hypothalamic glucagon signaling inhibits hepatic glucose production. Nat. Med. 19, 766–772 (2013). [PubMed]

D. S. Edgerton, A. D. Cherrington, Glucagon’s yin and yang effects on hepatic glucose production. Nat. Med. 19, 674-675 (2013). [PubMed]

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