A carnosine analog mitigates metabolic disorders of obesity by reducing carbonyl stress
Ethan J. Anderson, … , Marina Carini, Giancarlo Aldini
Ethan J. Anderson, … , Marina Carini, Giancarlo Aldini
Published December 3, 2018; First published September 18, 2018
Citation Information: J Clin Invest. 2018;128(12):5280-5293. https://doi.org/10.1172/JCI94307.
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Categories: Research Article Endocrinology Metabolism

A carnosine analog mitigates metabolic disorders of obesity by reducing carbonyl stress

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.

Authors

Ethan J. Anderson, Giulio Vistoli, Lalage A. Katunga, Katsuhiko Funai, Luca Regazzoni, T. Blake Monroe, Ettore Gilardoni, Luca Cannizzaro, Mara Colzani, Danilo De Maddis, Giuseppe Rossoni, Renato Canevotti, Stefania Gagliardi, Marina Carini, Giancarlo Aldini

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Figure 5

Therapeutic effect of carnosinol on metabolic homeostasis and carbonyl stress in mouse models of diet-induced obesity.

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Therapeutic effect of carnosinol on metabolic homeostasis and carbonyl s...
The effect of a HFHS diet with and without carnosinol treatment is shown for glucose tolerance (A–C, n = 8) and insulin sensitivity of EDL (D) and soleus muscle (E) tissue upon termination of the study for each group (n = 6). Representative immunoblots for HNE adducts in whole-tissue homogenates prepared from mixed gastrocnemius skeletal muscle (F) and pancreas (H) tissue (n = 3 mice per group), along with the corresponding densitometric analysis (G and I). †P < 0.01 versus control diet within each respective genotype. A 2-way ANOVA followed by Tukey’s multiple comparisons test was used to test for the main effect of the treatment within each genotype.