Journal article
A carnosine analog mitigates metabolic disorders of obesity by reducing carbonyl stress
The Journal of clinical investigation, Vol.128(12), pp.5280-5293
12/03/2018
DOI: 10.1172/JCI94307
PMCID: PMC6264636
PMID: 30226473
Abstract
Sugar- and lipid-derived aldehydes are reactive carbonyl species (RCS) frequently used as surrogate markers of oxidative stress in obesity. A pathogenic role for RCS in metabolic diseases of obesity remains controversial, however, partly because of their highly diffuse and broad reactivity and the lack of specific RCS-scavenging therapies. Naturally occurring histidine dipeptides (e.g., anserine and carnosine) show RCS reactivity, but their therapeutic potential in humans is limited by serum carnosinases. Here, we present the rational design, characterization, and pharmacological evaluation of carnosinol, i.e., (2S)-2-(3-amino propanoylamino)-3-(1H-imidazol-5-yl)propanol, a derivative of carnosine with high oral bioavailability that is resistant to carnosinases. Carnosinol displayed a suitable ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and was determined to have the greatest potency and selectivity toward α,β-unsaturated aldehydes (e.g., 4-hydroxynonenal, HNE, ACR) among all others reported thus far. In rodent models of diet-induced obesity and metabolic syndrome, carnosinol dose-dependently attenuated HNE adduct formation in liver and skeletal muscle, while simultaneously mitigating inflammation, dyslipidemia, insulin resistance, and steatohepatitis. These improvements in metabolic parameters with carnosinol were not due to changes in energy expenditure, physical activity, adiposity, or body weight. Collectively, our findings illustrate a pathogenic role for RCS in obesity-related metabolic disorders and provide validation for a promising new class of carbonyl-scavenging therapeutic compounds rationally derived from carnosine.
Details
- Title: Subtitle
- A carnosine analog mitigates metabolic disorders of obesity by reducing carbonyl stress
- Creators
- Ethan J Anderson - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USAGiulio Vistoli - Department of Pharmaceutical Sciences, University of Milan, Milan, ItalyLalage A Katunga - Department of Pharmacology and Toxicology, East Carolina University, Greenville, North Carolina, USAKatsuhiko Funai - Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, Utah, USALuca Regazzoni - Department of Pharmaceutical Sciences, University of Milan, Milan, ItalyT. Blake Monroe - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USAEttore Gilardoni - Department of Pharmaceutical Sciences, University of Milan, Milan, ItalyLuca Cannizzaro - Department of Pharmaceutical Sciences, University of Milan, Milan, ItalyMara Colzani - Department of Pharmaceutical Sciences, University of Milan, Milan, ItalyDanilo De Maddis - Department of Pharmaceutical Sciences, University of Milan, Milan, ItalyGiuseppe Rossoni - Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, ItalyRenato Canevotti - Flamma S.p.A., Chignolo d’Isola, Bergamo, ItalyStefania Gagliardi - Flamma S.p.A., Chignolo d’Isola, Bergamo, ItalyMarina Carini - Department of Pharmaceutical Sciences, University of Milan, Milan, ItalyGiancarlo Aldini - Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.128(12), pp.5280-5293
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/JCI94307
- PMID
- 30226473
- PMCID
- PMC6264636
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- L.297–Art. 12/BioTech DM27909; decree n. 6737 July; 2nd 2009 / MIUR-Regione Lombardia R21AG05,006 / ; R01HL122863 / ;
- Language
- English
- Date published
- 12/03/2018
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Fraternal Order of Eagles Diabetes Research Center; Health and Human Physiology
- Record Identifier
- 9984065317202771
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