Retinoic Acid Treatment Increases Lipid Oxidation Capacity in Skeletal Muscle of Mice

Laboratory of Molecular Biology, Nutrition and Biotechnology, Universitat de les Illes Balears, Palma de Mallorca, Spain.
Obesity (Impact Factor: 3.73). 04/2008; 16(3):585-91. DOI: 10.1038/oby.2007.104
Source: PubMed


All-trans retinoic acid (ATRA), a carboxylic form of vitamin A, favors in mice a mobilization of body fat reserves that correlates with an increment of oxidative and thermogenic capacity in adipose tissues. The objective of this study has been to investigate the effect of ATRA treatment on skeletal muscle capacity for fatty-acid catabolism.
Tissue composition and gene expression related to lipid and oxidative metabolism were analyzed in skeletal muscle of mice acutely treated with ATRA or vehicle (olive oil).
ATRA treatment triggered a dose-dependent increase in the muscle mRNA expression levels of selected enzymes, transporters and transcription factors involved in fatty-acid oxidation, respiration, and thermogenesis namely: muscle-type carnitine palmitoyltransferase 1, acyl CoA oxidase 1, subunit II of cytochrome oxidase, uncoupling protein 3, peroxisome proliferator-activated receptor-gamma co-activator -1alpha and peroxisome proliferator-activated receptor-delta (PPARdelta). The treatment also resulted in the upregulation of the mRNA levels of acetyl-CoA carboxylase 2 (ACC2), a key regulatory enzyme for mitochondrial fatty-acid oxidation in muscle. Skeletal muscle protein levels of PPARdelta and retinoid X receptor gamma, a partner for many nuclear receptors involved in lipid metabolism, were increased after ATRA treatment. Muscle lipid content was decreased.
These results indicate that ATRA treatment increases the capacity of skeletal muscle for fatty-acid oxidation. Knowledge of nutrients or nutrient-derivatives capable of enhancing oxidative metabolism in muscle and other tissues can contribute to new avenues of prevention and treatment of obesity and related disorders.

Download full-text


Available from: M. Luisa Bonet, Apr 29, 2014
  • Source
    • "(For interpretation of the references to color in this figure, the reader is referred to the Web version of this article.) this vitamin had been linked to lipid metabolism [67] and is known to increase fatty acid oxidation in muscle in mice [68], its inhibition at 60 days could be linked to the high energy demands of the lactation peak, which would explain why cows with a greater NEB are more affected. Vitamin D, apart from its well-known role in calcium metabolism, has an antiproliferative effect and stimulates the differentiation of several cell types [69]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dairy cows expend great amounts of energy during the lactation peak to cope with milk production. A state of negative energy balance (NEB) was suggested as a cause for the suboptimal fertility observed during this period, via an interaction with ovarian function. The objective of this study was to identify the impact of NEB on gene expression in granulosa cells of dairy cows at 60 days postpartum and to suggest a potential treatment to improve ovarian function. Dairy cows at 60 days postpartum from 10 typical medium-sized farms were synchronized using a single injection of prostaglandin. Dominant follicles were collected 42 hours later by transvaginal aspiration. Blood concentrations of beta-hydroxybutyrate (BHB) on the day of aspiration were used to classify animals into two groups: severe NEB (high BHB, n = 12) and mild NEB (low BHB, n = 12). The transcriptomes of granulosa cells from both groups were contrasted using microarrays, and the differentially expressed genes were analyzed using Ingenuity Pathway Analysis to identify affected functions and potential upstream regulators. Genes linked with cellular organization (KRT4 and PPL), proliferation (TACSTD2), and fatty acids metabolism (VNN2) were downregulated in granulosa cells from animals with severe NEB. Several genes linked to decitabine, a hypomethylating agent, and with beta-estradiol, were downregulated in the severe NEB group. Numerous genes linked to vitamins A and D were also downregulated in this group of cows, suggesting a potential deficiency of these vitamins in dairy cows during the postpartum period. This study supports the idea that energy balance has an impact on follicular dynamics which could be detrimental to resumption of fertility after calving. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Jul 2015 · Theriogenology
  • Source
    • "Retinoic acid-vitamin A metabolites exerts a number of essential biological functions through activation of two classes of nuclear receptors , RAR (α, β and γ), which respond to all-trans retinoic acid (ATRA) and 9-cis-isomers of RA; and RXR (α, β and γ), which are activated by 9-cis-RA exclusively. Studies have shown that ATRA inhibits the development of type 1 diabetes [6]; and reduces body weight and adiposity through regulation of lipid metabolism in the adipose tissue, liver and skeletal muscle of mice [7] [8] [9]. RXR agonists also have anti-diabetic effects in type 2 diabetic mouse models [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Diabetic cardiomyopathy (DCM) is a significant contributor to the morbidity and mortality associated with diabetes and metabolic syndrome. Retinoids, through activation of retinoic acid receptor (RAR) and retinoid x receptor (RXR), have been linked to control of glucose and lipid homeostasis, with effects on obesity and diabetes. However, the functional role of RAR and RXR in the development of DCM remains unclear. Zucker diabetic fatty (ZDF) and lean rats were treated with Am580 (RARα agonist) or LGD1069 (RXR agonist) for 16 weeks, and cardiac function and metabolic alterations were determined. Hyperglycemia, hyperlipidemia and insulin resistance were observed in ZDF rats. Diabetic cardiomyopathy was characterized in ZDF rats by increased oxidative stress, apoptosis, fibrosis, inflammation, activation of MAP kinases and NF-κB signaling and diminished Akt phosphorylation, along with decreased glucose transport and increased cardiac lipid accumulation, and ultimately diastolic dysfunction. Am580 and LGD1069 attenuated diabetes-induced cardiac dysfunction and the pathological alterations, by improving glucose tolerance and insulin resistance; facilitating Akt activation and glucose utilization, and attenuating oxidative stress and interrelated MAP kinase and NF-κB signaling pathways. Am580 inhibited body weight gain, attenuated the increased cardiac fatty acid uptake, β-oxidation and lipid accumulation in the hearts of ZDF rats. However, LGD1069 promoted body weight gain, hyperlipidemia and cardiac lipid accumulation. In conclusion, our data suggest that activation of RAR and RXR may have therapeutic potential in the treatment of diabetic cardiomyopathy. However, further studies are necessary to clarify the role of RAR and RXR in the regulation of lipid metabolism and homeostasis.
    Full-text · Article · Feb 2013 · Journal of Molecular and Cellular Cardiology
  • Source
    • "Several ALDH enzymes, including Aldh1a1, Aldh1a2 and Aldh1a3 in humans, catalyze the irreversible oxidation of vitamin A (VA) to retinoic acid (RA), which binds and activates nuclear retinoic acid receptor (RAR)/retinoid X receptor (RXR) heterodimers to regulate the transcription of target genes that are important for development, morphogenesis and differentiation (Jackson et al., 2011; Samarut and Rochette-Egly, 2012). Many studies have been conducted to analyze the role of RA in muscle development and have shown that RA exerts a direct effect on skeletal muscle differentiation as well as on the metabolism of murine, zebrafish and chicken skeletal muscle cells (Albagli-Curiel et al., 1993; Amengual et al., 2008; Hamade et al., 2006; Maden et al., 2000; Reijntjes et al., 2009). However, the effect of RA on oxidative stress and survival of skeletal muscle cells has not been determined. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Protection of satellite cells from cytotoxic damages is a critical issue to ensure efficient adult skeletal muscle regeneration and to improve therapeutic efficacy of cell transplantation in degenerative skeletal muscle diseases. It is therefore important to identify and characterize molecules and their target genes that control the viability of muscle stem cells. Recently, we demonstrated that high aldehyde dehydrogenase activity is associated with increased viability of human myoblasts. In addition to its detoxifying activity, aldehyde dehydrogenase can also catalyze the irreversible oxidation of vitamin A to retinoic acid; therefore, we examined whether retinoic acid is important for myoblast viability. We showed that when exposed to oxidative stress induced by hydrogen peroxide, adherent human myoblasts entered apoptosis and lost their capacity for adhesion. Pre-treatment with retinoic acid reduced these cytotoxic damages ex vivo and enhanced myoblast survival in transplantation assays. The effects of retinoic acid were maintained in dystrophic myoblasts derived from Facioscapulohumeral patients. RT-qPCR analysis of antioxidant gene expression revealed glutathione peroxidase 3, a gene encoding an antioxidant enzyme, as a potential retinoic acid target gene in human myoblasts. Knockdown of glutathione peroxidase 3 via siRNA induced elevation in reactive oxygen species and cell death. The anti-cytotoxic effects of retinoic acid were impaired in GPx3 inactivated myoblasts, which indicates that GPx3 regulates the antioxidative effects of retinoic acid. Therefore, retinoid status and GPx3 levels may have important implications for the viability of human muscle stem cells.
    Full-text · Article · Nov 2012 · Journal of Cell Science
Show more