Beretta, Martina and Dai, Yumin and Olzomer, Ellen M. and Vancuylenburg, Calum S. and Santiago-Rivera, José A. and Philp, Ashleigh M. and Hargett, Stefan R. and Li, Keyong and Shah, Divya P. and Chen, Sing-Young and Alexopoulos, Stephanie J. and Li, Catherine and Harris, Thurl E. and Lee, Brendan and Wathier, Michel and Cermak, Jennifer M. and Tucker, Simon P. and Turner, Nigel and Bayliss, Douglas A. and Philp, Andrew and Byrne, Frances L. and Santos, Webster L. and Hoehn, Kyle L. (2024) Liver-Selective Imidazolopyrazine Mitochondrial Uncoupler SHD865 Reverses Adiposity and Glucose Intolerance in Mice. Diabetes, 73 (3). pp.374-384. ISSN 0012-1797
Full text not available from this repository.Abstract
Excess body fat is a risk factor for metabolic diseases and is a leading preventable cause of morbidity and mortality worldwide. There is a strong need to find new treatments that decrease the burden of obesity and lower the risk of obesity-related comorbidities, including cardiovascular disease and type 2 diabetes. Pharmacologic mitochondrial uncouplers represent a potential treatment for obesity through their ability to increase nutrient oxidation. Herein, we report the in vitro and in vivo characterization of compound SHD865, the first compound to be studied in vivo in a newly discovered class of imidazolopyrazine mitochondrial uncouplers. SHD865 is a derivative of the furazanopyrazine uncoupler BAM15. SHD865 is a milder mitochondrial uncoupler than BAM15 that results in a lower maximal respiration rate. In a mouse model of diet-induced adiposity, 6-week treatment with SHD865 completely restored normal body composition and glucose tolerance to levels like those of chow-fed controls, without altering food intake. SHD865 treatment also corrected liver steatosis and plasma hyperlipidemia to normal levels comparable with chow-fed controls. SHD865 has maximal oral bioavailability in rats and slow clearance in human microsomes and hepatocytes. Collectively, these data identify the potential of imidazolopyrazine mitochondrial uncouplers as drug candidates for the treatment of obesity-related disorders.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 13 Dec 2024 05:28 |
| Last Modified: | 14 Dec 2024 01:41 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/1504 |
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