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Cited by 135Liver Disease Diagnosis and TreatmentPancreatic function and diabetesAmino Acid Enzymes and Metabolism

Glucagon acutely regulates hepatic amino acid catabolism and the effect may be disturbed by steatosis

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Winther-Sørensen, Marie, Galsgaard, Katrine D., Santos, Alberto, Trammell, Samuel A.J., Sulek, Karolina, Kuhre, Rune E., Pedersen, Jens, Andersen, Daniel B. +19 more·2020·Molecular Metabolism
DOI 10.1016/j.molmet.2020.101080PMC PMC7560169
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Abstract

OBJECTIVE: Glucagon is well known to regulate blood glucose but may be equally important for amino acid metabolism. Plasma levels of amino acids are regulated by glucagon-dependent mechanism(s), while amino acids stimulate glucagon secretion from alpha cells, completing the recently described liver-alpha cell axis. The mechanisms underlying the cycle and the possible impact of hepatic steatosis are unclear. METHODS: We assessed amino acid clearance in vivo in mice treated with a glucagon receptor antagonist (GRA), transgenic mice with 95% reduction in alpha cells, and mice with hepatic steatosis. In addition, we evaluated urea formation in primary hepatocytes from ob/ob mice and humans, and we studied acute metabolic effects of glucagon in perfused rat livers. We also performed RNA sequencing on livers from glucagon receptor knock-out mice and mice with hepatic steatosis. Finally, we measured individual plasma amino acids and glucagon in healthy controls and in two independent cohorts of patients with biopsy-verified non-alcoholic fatty liver disease (NAFLD). RESULTS: Amino acid clearance was reduced in mice treated with GRA and mice lacking endogenous glucagon (loss of alpha cells) concomitantly with reduced production of urea. Glucagon administration markedly changed the secretion of rat liver metabolites and within minutes increased urea formation in mice, in perfused rat liver, and in primary human hepatocytes. Transcriptomic analyses revealed that three genes responsible for amino acid catabolism (Cps1, Slc7a2, and Slc38a2) were downregulated both in mice with hepatic steatosis and in mice with deletion of the glucagon receptor. Cultured ob/ob hepatocytes produced less urea upon stimulation with mixed amino acids, and amino acid clearance was lower in mice with hepatic steatosis. Glucagon-induced ureagenesis was impaired in perfused rat livers with hepatic steatosis. Patients with NAFLD had hyperglucagonemia and increased levels of glucagonotropic amino acids, including alanine in particular. Both glucagon and alanine levels were reduced after diet-induced reduction in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR, a marker of hepatic steatosis). CONCLUSIONS: Glucagon regulates amino acid metabolism both non-transcriptionally and transcriptionally. Hepatic steatosis may impair glucagon-dependent enhancement of amino acid catabolism.

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  • GcgR mediated amino acid catabolism and muscle wasting potentially contribute to the weight-loss phenomenon of 16 in this preclinical study.

    “This phenomenon appears to be positively correlated to in vitro GcgR potency, indicating a potential contribution of GcgR mediated amino acid catabolism and muscle wasting to the weight-loss phenomenon of 16 in this preclinical study [75], while elevated glycogenolysis and gluconeogenesis may contribute to the glucose control outcome [75].”

    From Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice (2022) · cites this paper as [75]

    The Results section on glucagon-receptor knockout mice and the Conclusion support a role for glucagon-receptor signaling in hepatic amino acid catabolism. They do not establish muscle wasting or weight loss caused by compound 16; the weight-loss cohort in the Results underwent calorie restriction. The copy also does not establish that elevated glycogenolysis or gluconeogenesis explains compound 16’s glucose-control outcome. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Elevated glycogenolysis and gluconeogenesis may contribute to the glucose control outcome of 16.

    “This phenomenon appears to be positively correlated to in vitro GcgR potency, indicating a potential contribution of GcgR mediated amino acid catabolism and muscle wasting to the weight-loss phenomenon of 16 in this preclinical study [75], while elevated glycogenolysis and gluconeogenesis may contribute to the glucose control outcome [75].”

    From Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice (2022) · cites this paper as [75]

    The Introduction (page unavailable) says glucagon increases hepatic glucose production, and the Conclusion (page unavailable) describes preserved hyperglycemic effects of glucagon in the setting studied. The paper does not identify elevated glycogenolysis or gluconeogenesis as the mechanisms, or address the glucose-control outcome of compound 16. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • The reduction in lean mass and glucose control by compound 16 appears to be positively correlated to in vitro GcgR potency.

    “This phenomenon appears to be positively correlated to in vitro GcgR potency, indicating a potential contribution of GcgR mediated amino acid catabolism and muscle wasting to the weight-loss phenomenon of 16 in this preclinical study [75], while elevated glycogenolysis and gluconeogenesis may contribute to the glucose control outcome [75].”

    From Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice (2022) · cites this paper as [75]

    The Results on glucagon-receptor knockout mice and the Discussion support a role for GcgR signaling in hepatic amino acid catabolism; the Discussion also reports lower baseline blood glucose after receptor antagonism. But the paper does not establish a correlation between in vitro GcgR potency and compound 16’s effects, or link its amino acid findings to muscle wasting and loss of lean mass. The cited passages also do not identify glycogenolysis or gluconeogenesis as the cause of the stated glucose-control outcome. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Authors
Winther-Sørensen, M., Galsgaard, K. D., Santos, A., Trammell, S. A. J., Sulek, K., Kuhre, R. E., Pedersen, J., Andersen, D. B., Hassing, A. S., Dall, M., Treebak, J. T., Gillum, M. P., Torekov, S. S., Windeløv, J. A., Hunt, J. E., Kjeldsen, S. A. S., Jepsen, S. L., Vasilopoulou, C. G., Knop, F. K., Ørskov, C., Werge, M. P., Bisgaard, H. C., Eriksen, P. L., Vilstrup, H., Gluud, L. L., Holst, J. J., & Wewer Albrechtsen, N. J.
Affiliations
  • University of Copenhagen (DK)
  • Max Planck Institute of Biochemistry (DE)
  • Aarhus University Hospital (DK)
Corresponding author
Holst, Jens J.
ORCID
Venue
Molecular Metabolism
Publisher
Elsevier BV
Published
2020-12
Volume
42
Pages
101080
ISSN
2212-8778 (ISSN-L)
DOI
10.1016/j.molmet.2020.101080
PMC
PMC7560169
OpenAlex
W3085056884
Cited by
135
References
4
Citations by year
2026: 29 · 2025: 20 · 2024: 20 · 2023: 24 · 2022: 26 · 2021: 14 · 2020: 2
FWCI
11.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Metabolism (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
Funders
  • Novo Nordisk Fonden (NNF19OC0055001, 34250, 31526, NNF14CC0001)
  • Københavns Universitet
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords
glucagon, hepatic steatosis, non-alcoholic fatty liver disease, urea synthesis, urea formation, glucagon receptor, alpha cells, alanine, hyperglucagonemia, insulin resistance, CPS1, SLC7A2, SLC38A2, hepatocytes, plasma amino acids
MeSH terms
Adult, Amino Acids, Animals, Blood Glucose, Fatty Liver, Female, Glucagon, Glucose, Humans, Insulin, Insulin Resistance, Liver, Male, Mice, Inbred C57BL, Middle Aged, Urea, Rats, Wistar, Receptors, Glucagon, Hepatocytes, Glucagon-Secreting Cells, Mice, Rats, Non-alcoholic Fatty Liver Disease

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