TY - JOUR
T1 - Opposing effects of chronic glucagon receptor agonism and antagonism on amino acids, hepatic gene expression, and alpha cells
AU - Elmelund, Emilie
AU - Galsgaard, Katrine D.
AU - Johansen, Christian D.
AU - Trammell, Samuel A.J.
AU - Bomholt, Anna B.
AU - Winther-Sørensen, Marie
AU - Hunt, Jenna E.
AU - Sørensen, Charlotte M.
AU - Kruse, Thomas
AU - Lau, Jesper F.
AU - Grevengoed, Trisha J.
AU - Holst, Jens J.
AU - Wewer Albrechtsen, Nicolai J.
N1 - Publisher Copyright:
© 2022 The Author(s)
PY - 2022
Y1 - 2022
N2 - The pancreatic hormone, glucagon, is known to regulate hepatic glucose production, but recent studies suggest that its regulation of hepatic amino metabolism is equally important. Here, we show that chronic glucagon receptor activation with a long-acting glucagon analog increases amino acid catabolism and ureagenesis and causes alpha cell hypoplasia in female mice. Conversely, chronic glucagon receptor inhibition with a glucagon receptor antibody decreases amino acid catabolism and ureagenesis and causes alpha cell hyperplasia and beta cell loss. These effects were associated with the transcriptional regulation of hepatic genes related to amino acid uptake and catabolism and by the non-transcriptional modulation of the rate-limiting ureagenesis enzyme, carbamoyl phosphate synthetase-1. Our results support the importance of glucagon receptor signaling for amino acid homeostasis and pancreatic islet integrity in mice and provide knowledge regarding the long-term consequences of chronic glucagon receptor agonism and antagonism.
AB - The pancreatic hormone, glucagon, is known to regulate hepatic glucose production, but recent studies suggest that its regulation of hepatic amino metabolism is equally important. Here, we show that chronic glucagon receptor activation with a long-acting glucagon analog increases amino acid catabolism and ureagenesis and causes alpha cell hypoplasia in female mice. Conversely, chronic glucagon receptor inhibition with a glucagon receptor antibody decreases amino acid catabolism and ureagenesis and causes alpha cell hyperplasia and beta cell loss. These effects were associated with the transcriptional regulation of hepatic genes related to amino acid uptake and catabolism and by the non-transcriptional modulation of the rate-limiting ureagenesis enzyme, carbamoyl phosphate synthetase-1. Our results support the importance of glucagon receptor signaling for amino acid homeostasis and pancreatic islet integrity in mice and provide knowledge regarding the long-term consequences of chronic glucagon receptor agonism and antagonism.
KW - Biological sciences
KW - Endocrinology
KW - Transcriptomics
U2 - 10.1016/j.isci.2022.105296
DO - 10.1016/j.isci.2022.105296
M3 - Journal article
C2 - 36325048
AN - SCOPUS:85140355202
VL - 25
JO - iScience
JF - iScience
SN - 2589-0042
IS - 11
M1 - 105296
ER -