Hypoaminoacidemia underpins glucagon-mediated energy expenditure and weight loss
| Autor: | Hope, David C D, Hinds, Charlotte E, Lopes, Tatiana, Vincent, Matthew L, Shrewsbury, Jed V, Yu, Arthur T C, Davies, Iona, Scott, Rebecca, Jones, Ben, Murphy, Kevin G, Minnion, James S, Sardini, Alessandro, Carling, David, Lutz, Thomas A, Bloom, Stephen R, Tan, Tricia M M, Owen, Bryn M |
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| Přispěvatelé: | University of Zurich, Tan, Tricia M M, Owen, Bryn M |
| Rok vydání: | 2022 |
| Předmět: |
Mice
Obese Genetics and Molecular Biology Glucagon 10081 Institute of Veterinary Physiology General Biochemistry Genetics and Molecular Biology Mice 1300 General Biochemistry Genetics and Molecular Biology Weight Loss General Biochemistry Receptors Glucagon Animals 570 Life sciences biology Amino Acids Energy Metabolism |
| DOI: | 10.5167/uzh-231099 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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