Opposing effects of chronic glucagon receptor agonism and antagonism on amino acids, hepatic gene expression, and alpha cells

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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.

OriginalsprogEngelsk
Artikelnummer105296
TidsskriftiScience
Vol/bind25
Udgave nummer11
Antal sider20
ISSN2589-0042
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
We thank Regeneron for providing the antibodies REGN1193 and REGN1945. We thank Maureen J. Charron, Departments of Biochemistry, Obstetrics and Gynecology and Women's Health, and Medicine, Albert Einstein College of Medicine, New York, for providing glucagon receptor knockout mice. We thank the Center for Genomic Medicine, Rigshospitalet, Denmark for performing RNA sequencing. We thank laboratory technician Heidi Marie Paulsen for the preparation and staining of pancreas slices and Associate Professor Jens Brings Jacobsen for access to his microscope. This work was supported by the Novo Nordisk Foundation (NNF) Center for Basic Metabolic Research University of Copenhagen, (NNF Application Number: 13563); NNF Project Support in Endocrinology and Metabolism-Nordic Region (NNF Application Number: 34250). Emilie Elmelund is supported by the Novo Scholarship Program (2022). Nicolai J. Wewer Albrechtsen is supported by an NNF Excellence Emerging Investigator Grant – Endocrinology and Metabolism (NNF19OC0055001), EFSD Future Leader Award (NNF21SA0072746) and Independent Research Fund, Sapere Aude (1052-00003B). Novo Nordisk Foundation Center for Protein Research is supported by the Novo Nordisk Foundation (grant agreement NNF14CC0001). The data were presented at American Diabetes Association's 82nd Scientific Session, June 3rd -7th, New Orleans, LA, USA. The graphical abstract is created with BioRender.com. Conceptualization, K.D.G. J.J.H. N.J.W.A.; resources, T.K. J.F.L.; investigation, E.E. K.D.G. A.B.B. J.E.H. S.A.J.T.; formal analysis, E.E. K.D.G. C.D.J.; visualization, E.E. K.D.G. C.D.J.; writing – original draft, E.E.; writing – review & editing, K.D.G. C.D.J. S.A.J.T. A.B.B. M.W.S. J.E.H. C.M.S. T.K. J.F.L, T.J.G. J.J.H. N.J.W.A.; supervision and funding acquisition, J.J.H. N.J.W.A. All authors approved the final version of the article. Thomas Kruse and Jesper F. Lau are employed by Novo Nordisk A/S. No conflicts of interest, financial or otherwise, are declared by the remaining authors.

Funding Information:
We thank Regeneron for providing the antibodies REGN1193 and REGN1945. We thank Maureen J. Charron, Departments of Biochemistry, Obstetrics and Gynecology and Women’s Health, and Medicine, Albert Einstein College of Medicine, New York, for providing glucagon receptor knockout mice. We thank the Center for Genomic Medicine, Rigshospitalet, Denmark for performing RNA sequencing. We thank laboratory technician Heidi Marie Paulsen for the preparation and staining of pancreas slices and Associate Professor Jens Brings Jacobsen for access to his microscope. This work was supported by the Novo Nordisk Foundation (NNF) Center for Basic Metabolic Research University of Copenhagen , (NNF Application Number: 13563 ); NNF Project Support in Endocrinology and Metabolism-Nordic Region (NNF Application Number: 34250 ). Emilie Elmelund is supported by the Novo Scholarship Program (2022). Nicolai J. Wewer Albrechtsen is supported by an NNF Excellence Emerging Investigator Grant – Endocrinology and Metabolism ( NNF19OC0055001 ), EFSD Future Leader Award ( NNF21SA0072746 ) and Independent Research Fund , Sapere Aude ( 1052-00003B ). Novo Nordisk Foundation Center for Protein Research is supported by the Novo Nordisk Foundation (grant agreement NNF14CC0001 ). The data were presented at American Diabetes Association’s 82 nd Scientific Session, June 3 rd -7 th , New Orleans, LA, USA. The graphical abstract is created with BioRender.com .

Publisher Copyright:
© 2022 The Author(s)

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