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Hypoaminoacidemia underpins glucagon-mediated energy expenditure and weight loss

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Title: Hypoaminoacidemia underpins glucagon-mediated energy expenditure and weight loss
Authors: Hope, D
Hinds, C
Lopes, T
Vincent, M
Shrewsbury, J
Yu, A
Davies, I
Scott, R
Jones, B
Murphy, K
Minnion, J
Sardini, A
Carling, D
Lutz, T
Bloom, S
Tan, T
Owen, B
Item Type: Journal Article
Abstract: Glucagon analogues show promise as components of next-generation, multi-target, anti-obesity therapeutics. The biology of chronic glucagon treatment, in particular its ability to induce energy expenditure and weight loss, remains poorly understood. Using a long-acting glucagon analogue, G108, we demonstrate that glucagon-mediated body weight loss is intrinsically linked to the hypoaminoacidemia associated with its known amino acid catabolic action. Mechanistic studies reveal an energy-consuming response to low plasma amino acids in G108-treated mice, prevented by dietary amino acid supplementation and mimicked by a rationally designed low amino acid diet. Therefore, low plasma amino acids are a prerequisite for G108-mediated energy expenditure and weight loss. However, preventing hypoaminoacidemia with additional dietary protein does not affect the ability of G108 to improve glycemia or hepatic steatosis in obese mice. These studies provide a mechanism for glucagon-mediated weight loss and confirm the hepatic glucagon receptor as an attractive molecular target for metabolic disease therapeutics.
Issue Date: 15-Nov-2022
Date of Acceptance: 18-Oct-2022
URI: http://hdl.handle.net/10044/1/101046
DOI: 10.1016/j.xcrm.2022.100810
ISSN: 2666-3791
Publisher: Cell Press
Journal / Book Title: Cell Reports Medicine
Volume: 3
Issue: 11
Copyright Statement: © 2022 The Author(s). his is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Publication Status: Published
Article Number: ARTN 100810
Online Publication Date: 2022-11-15
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Institute of Clinical Sciences

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