Novel Markers of the Metabolic Impact of Exogenous Retinoic Acid with A Focus on Acylcarnitines and Amino Acids.

Joan Ribot,Andrea Arreguín,Ondrej Kuda,Andreu Palou,Jan Kopecky,Maria Luisa Bonet

doi:10.3390/ijms20153640

Abstract

Treatment with all-trans retinoic acid (ATRA), the carboxylic form of vitamin A, lowers body weight in rodents by promoting oxidative metabolism in multiple tissues including white and brown adipose tissues. We aimed to identify novel markers of the metabolic impact of ATRA through targeted blood metabolomics analyses, with a focus on acylcarnitines and amino acids. Blood was obtained from mice treated with a high ATRA dose (50 mg/kg body weight/day, subcutaneous injection) or placebo (controls) during the 4 days preceding collection. LC-MS/MS analyses with a focus on acylcarnitines and amino acids were conducted on plasma and PBMC. Main results showed that, relative to controls, ATRA-treated mice had in plasma: increased levels of carnitine, acetylcarnitine, and longer acylcarnitine species; decreased levels of citrulline, and increased global arginine bioavailability ratio for nitric oxide synthesis; increased levels of creatine, taurine and docosahexaenoic acid; and a decreased n-6/n-3 polyunsaturated fatty acids ratio. While some of these features likely reflect the stimulation of lipid mobilization and oxidation promoted by ATRA treatment systemically, other may also play a causal role underlying ATRA actions. The results connect ATRA to specific nutrition-modulated biochemical pathways, and suggest novel mechanisms of action of vitamin A-derived retinoic acid on metabolic health.

Highlights

Substrate oxidation coupled to the generation of either ATP or heat opposes body fat gain and contributes to decreased levels of circulating lipids and glucose
We here identified through targeted metabolomics changes in circulating markers in response to a short-term, high-dose All-trans retinoic acid (ATRA) treatment in mice that may give further clues about the mechanisms of ATRA action on metabolic health and energy and lipid metabolism in mammalian tissues, notably the adipose tissues
We favor the first interpretation because ATRA treatment increases ketone body production and blood levels [12], while it had no effect on the circulating levels of valine (Figure 2) or AC C3:0 and AC C5:0 (Figure 1), which are ACs produced during the catabolism of valine and other branched-chain amino acids (AA)

Summary

Introduction

Substrate oxidation coupled to the generation of either ATP or heat opposes body fat gain and contributes to decreased levels of circulating lipids and glucose. ATRA effects on lipid and energy metabolism are mediated by multiple mechanisms, including the activation of specific nuclear receptors (notably the canonical RARs and the β/δ isoform of peroxisome proliferator-activated receptor, PPAR β/δ), protein kinases, and hormonal pathways [10,11] Both in lean and obese ATRA-treated mice, decreases in body weight and adiposity and improvements in glucose tolerance, insulin sensitivity, blood lipids, and liver lipid content are observed [6,10,12,21,22]

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