Retinoic Acid Increases Fatty Acid Oxidation and Irisin Expression in Skeletal Muscle Cells and Impacts Irisin In Vivo

Background/Aims: All-trans retinoic acid (ATRA) has protective effects against obesity and metabolic syndrome. We here aimed to gain further insight into the interaction of ATRA with skeletal muscle metabolism and secretory activity as important players in metabolic health. Methods: Cultured murine C2C12 myocytes were used to study direct effects of ATRA on cellular fatty acid oxidation (FAO) rate (using radioactively-labelled palmitate), glucose uptake (using radioactively-labelled 2-deoxy-D-glucose), triacylglycerol levels (by an enzymatic method), and the expression of genes related to FAO and glucose utilization (by RT-real time PCR). We also studied selected myokine production (using ELISA and immunohistochemistry) in ATRA-treated myocytes and intact mice. Results: Exposure of C2C12 myocytes to ATRA led to increased fatty acid consumption and decreased cellular triacylglycerol levels without affecting glucose uptake, and induced the expression of the myokine irisin at the mRNA and secreted protein level in a dose-response manner. ATRA stimulatory effects on FAO-related genes and the Fndc5 gene (encoding irisin) were reproduced by agonists of peroxisome proliferator-activated receptor β/δ and retinoid X receptors, but not of retinoic acid receptors, and were partially blocked by an AMP-dependent protein kinase inhibitor. Circulating irisin levels were increased by 5-fold in ATRA-treated mice, linked to increased Fndc5 transcription in liver and adipose tissues, rather than skeletal muscle. Immunohistochemistry analysis of FNDC5 suggested that ATRA treatment enhances the release of FNDC5/irisin from skeletal muscle and the liver and its accumulation in interscapular brown and inguinal white adipose depots. Conclusion: These results provide new mechanistic insights on how ATRA globally stimulates FAO and enhances irisin secretion, thereby contributing to leaning effects and improved metabolic status.

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Abstract 344: FNDC5, a PGC1-a-Dependent Myokine, Increases Glucose Utilization and Fatty-Acid Oxidation by AMPK Signaling Pathway

Circulation Research ◽

10.1161/res.113.suppl_1.a344 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Ling Tao ◽

Yi Liu ◽

Chao Xin ◽

Weidong Huang ◽

Lijian Zhang ◽

...

Keyword(s):

Fatty Acid ◽

Glucose Uptake ◽

Fatty Acid Oxidation ◽

Glucose Utilization ◽

C2c12 Cells ◽

Time Dependent ◽

Acid Oxidation ◽

Ampk Signaling

FNDC5 is a hormone secreted by myocytes that could reduce obesity and insulin resistance, However, the exact effect of FNDC5 on glucose and lipid metabolism remain poorly identified; More importantly, the signaling pathways that mediate the metabolic effects of FNDC5 is completely unknown. Here we showed that FNDC5 stimulates β-oxidation and glucose uptake in C2C12 cells in a dose- and time-dependent fashion in vitro (n=8, all P<0.01). In vivo study revealed that FNDC5 also enhanced glucose tolerance in diabetic mice and increased the glucose uptake evidenced by increased [18F] FDG accumulation in hearts by PET scan (n=6, all P<0.05). FNDC5 decreased the expression of gluconeogenesis related molecules (PEPCK and G6Pase) and increased the phosphorylation of ACC, a key modulator of fatty-acid oxidation, both in hepatocytes and C2C12 cells (n=3, all P<0.05). In parallel with its stimulation of β-oxidation and glucose uptake, FNDC5 increased the phosphorylation of AMPK both in hepatocytes and C2C12 cells in a dose- and time-dependent fashion in vitro and in vivo. More importantly, the β-oxidation and glucose uptake, the expression of PEPCK and G6Pase and the phosphorylation of ACC induced by FNDC5 were attenuated by AMPK inhibitor in hepatocytes and C2C12 cells (P<0.05). Most importantly, the FNDC5 induced glucose uptake and phosphorylation of ACC were attenuated in AMPK-DN mice (n=6, all P<0.05). The glucose-lowering effect of FNDC5 in diabetic mice was also attenuated by AMPK inhibitor. Our data presents the direct evidence that FNDC5 stimulates glucose utilization and fatty-acid oxidation by AMPK signaling pathway, suggesting that FNDC5 be a novel pharmacological approach for type 2 diabetes.

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Fatty Acid Oxidation by Skeletal Muscle During Rest and Activity

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1958.194.2.379 ◽

1958 ◽

Vol 194 (2) ◽

pp. 379-386 ◽

Cited By ~ 154

Author(s):

Irving B. Fritz ◽

Don G. Davis ◽

Robert H. Holtrop ◽

Harold Dundee

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Palmitic Acid ◽

Fatty Acid Oxidation ◽

Latissimus Dorsi ◽

Acid Metabolism ◽

Fat Metabolism ◽

Acid Oxidation ◽

Stimulation Of

The metabolism of C14-labeled acetate, octanoate and palmitate by isolated skeletal muscle (latissimus dorsi and diaphragm) from normal, fed rats has been examined. The rates at which these substrates were converted to C14O2 have been shown to vary with concentration, temperature, functional state of the muscle, and the presence of albumin. Increased concentration of fatty acids led to enhanced conversion of substrate to C14O2. Electrical stimulation of muscles under tension resulted in approximately a 60% increase in oxygen consumption and about a 100% rise in fatty acid oxidation. The addition of glucose did not alter the rate of fatty acid metabolism by muscle. The addition of bovine albumin at concentrations up to approximately 1 µm albumin/7 µm palmitate resulted in augmented palmitic acid oxidation. However, at concentrations of albumin greater than 1 µm albumin/7 µm palmitate, palmitic acid degradation by resting diaphragm was inhibited, suggesting a firmer binding of fatty acid to albumin. The Q10 for palmitic acid oxidation by resting diaphragm was 2.23 in the absence of added albumin between 25° and 37°C. The data are discussed in relation to the present concepts of fat metabolism and transport in vivo. It is suggested that fat degradation in isolated muscle may provide an energy source during activity.

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AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.6.e1107 ◽

1997 ◽

Vol 273 (6) ◽

pp. E1107-E1112 ◽

Cited By ~ 226

Author(s):

G. F. Merrill ◽

E. J. Kurth ◽

D. G. Hardie ◽

W. W. Winder

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Protein Kinase ◽

Glucose Uptake ◽

Fatty Acid Oxidation ◽

Fold Increase ◽

Acid Oxidation ◽

Acetyl Coa Carboxylase ◽

Malonyl Coa ◽

Amp Activated Protein Kinase

5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) has previously been reported to be taken up into cells and phosphorylated to form ZMP, an analog of 5′-AMP. This study was designed to determine whether AICAR can activate AMP-activated protein kinase (AMPK) in skeletal muscle with consequent phosphorylation of acetyl-CoA carboxylase (ACC), decrease in malonyl-CoA, and increase in fatty acid oxidation. Rat hindlimbs were perfused with Krebs-Henseleit bicarbonate containing 4% bovine serum albumin, washed bovine red blood cells, 200 μU/ml insulin, and 10 mM glucose with or without AICAR (0.5–2.0 mM). Perfusion with medium containing AICAR was found to activate AMPK in skeletal muscle, inactivate ACC, and decrease malonyl-CoA. Hindlimbs perfused with 2 mM AICAR for 45 min exhibited a 2.8-fold increase in fatty acid oxidation and a significant increase in glucose uptake. No difference was observed in oxygen uptake in AICAR vs. control hindlimb. These results provide evidence that decreases in muscle content of malonyl-CoA can increase the rate of fatty acid oxidation.

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SUN-P009: Hemorrhagic Shock-Resuscitation Injury Decreases Fatty Acid Oxidation and Peroxisome Proliferator-Activated Receptor in the Skeletal Muscle

Clinical Nutrition ◽

10.1016/s0261-5614(16)30352-1 ◽

2016 ◽

Vol 35 ◽

pp. S48

Author(s):

L. Zhang ◽

X. Wang ◽

F. Tian ◽

X. Gao ◽

J. Li

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Hemorrhagic Shock ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

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Telmisartan increases fatty acid oxidation in skeletal muscle through a peroxisome proliferator-activated receptor-γ dependent pathway

Journal of Hypertension ◽

10.1097/hjh.0b013e3282f9b58a ◽

2008 ◽

Vol 26 (6) ◽

pp. 1209-1215 ◽

Cited By ~ 28

Author(s):

Ken Sugimoto ◽

Ludmila Kazdová ◽

Nathan R Qi ◽

Masaya Hyakukoku ◽

Vladimír Křen ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Dependent Pathway

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Transcriptome Changes of Skeletal Muscle RNA-Seq Speculates the Mechanism of Postprandial Hyperglycemia in Diabetic Goto-Kakizaki Rats During the Early Stage of T2D

Genes ◽

10.3390/genes10060406 ◽

2019 ◽

Vol 10 (6) ◽

pp. 406 ◽

Cited By ~ 2

Author(s):

Wenlu Zhang ◽

Yuhuan Meng ◽

Shuying Fu ◽

Xingsong Li ◽

Zixi Chen ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Glucose Uptake ◽

Fatty Acid Oxidation ◽

Wistar Rats ◽

Early Stage ◽

Postprandial Hyperglycemia ◽

Acid Oxidation ◽

Rna Seq ◽

Gk Rats

To address how skeletal muscle contributes to postprandial hyperglycemia, we performed skeletal muscle transcriptome analysis of diabetic Goto-Kakizaki (GK) and control Wistar rats by RNA sequencing (RNA-Seq). We obtained 600 and 1785 differentially expressed genes in GK rats compared to those Wistar rats at three and four weeks of age, respectively. Specifically, Tbc1d4, involved in glucose uptake, was significantly downregulated in the skeletal muscle of GK aged both three and four weeks compared to those of age-matched Wistar rats. Pdk4, related to glucose uptake and oxidation, was significantly upregulated in the skeletal muscle of GK aged both three and four weeks compared to that of age-matched Wistar rats. Genes (Acadl, Acsl1 and Fabp4) implicated in fatty acid oxidation were significantly upregulated in the skeletal muscle of GK aged four weeks compared to those of age-matched Wistar rats. The overexpression or knockout of Tbc1d4, Pdk4, Acadl, Acsl1 and Fabp4 has been reported to change glucose uptake and fatty acid oxidation directly in rodents. By taking the results of previous studies into consideration, we speculated that dysregulation of key dysregulated genes (Tbc1d4, Pdk4, Acadl, Acsl1 and Fabp4) may lead to a decrease in glucose uptake and oxidation, and an increase in fatty acid oxidation in GK skeletal muscle at three and four weeks, which may, in turn, contribute to postprandial hyperglycemia. Our research revealed transcriptome changes in GK skeletal muscle at three and four weeks. Tbc1d4, Acadl, Acsl1 and Fabp4 were found to be associated with early diabetes in GK rats for the first time, which may provide a new scope for pathogenesis of postprandial hyperglycemia.

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Estrogen-Related Receptor α Directs Peroxisome Proliferator-Activated Receptor α Signaling in the Transcriptional Control of Energy Metabolism in Cardiac and Skeletal Muscle

Molecular and Cellular Biology ◽

10.1128/mcb.24.20.9079-9091.2004 ◽

2004 ◽

Vol 24 (20) ◽

pp. 9079-9091 ◽

Cited By ~ 332

Author(s):

Janice M. Huss ◽

Inés Pineda Torra ◽

Bart Staels ◽

Vincent Giguère ◽

Daniel P. Kelly

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Target Genes ◽

Cellular Fatty Acid ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Oxidation Rates

ABSTRACT Estrogen-related receptors (ERRs) are orphan nuclear receptors activated by the transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), a critical regulator of cellular energy metabolism. However, metabolic target genes downstream of ERRα have not been well defined. To identify ERRα-regulated pathways in tissues with high energy demand such as the heart, gene expression profiling was performed with primary neonatal cardiac myocytes overexpressing ERRα. ERRα upregulated a subset of PGC-1α target genes involved in multiple energy production pathways, including cellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, and mitochondrial respiration. These results were validated by independent analyses in cardiac myocytes, C2C12 myotubes, and cardiac and skeletal muscle of ERRα−/− mice. Consistent with the gene expression results, ERRα increased myocyte lipid accumulation and fatty acid oxidation rates. Many of the genes regulated by ERRα are known targets for the nuclear receptor PPARα, and therefore, the interaction between these regulatory pathways was explored. ERRα activated PPARα gene expression via direct binding of ERRα to the PPARα gene promoter. Furthermore, in fibroblasts null for PPARα and ERRα, the ability of ERRα to activate several PPARα targets and to increase cellular fatty acid oxidation rates was abolished. PGC-1α was also shown to activate ERRα gene expression. We conclude that ERRα serves as a critical nodal point in the regulatory circuitry downstream of PGC-1α to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle.

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PGC-1α activator–induced fatty acid oxidation in tumor-infiltrating CTLs enhances effects of PD-1 blockade therapy in lung cancer

Tumori Journal ◽

10.1177/0300891619868287 ◽

2019 ◽

Vol 106 (1) ◽

pp. 55-63

Author(s):

Huan Wan ◽

Bin Xu ◽

Ni Zhu ◽

Baozhong Ren

Keyword(s):

Lung Cancer ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Tumor Model ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Programmed Death ◽

Effect Of Pd

Purpose: The present study aims to investigate the efficacy and mechanisms of peroxisome proliferator-activated receptor γ coactivator 1-α agonist, as adjuvant to programmed death-1 (PD-1) blockade in hyporesponsive lung cancer cells–derived in vivo tumor model, using bezafibrate. Methods: Mouse Lewis lung carcinoma (LLC) xenograft models were established and treated with programmed death-ligand 1 (PD-L1) monoclonal antibodies with or without bezafibrate. Tumors or peripheral blood of mice were harvested to investigate the quality, quantity, and function as well as energetic metabolism of cytotoxic T lymphocytes (CTLs) by flow cytometry or quantitative real-time polymerase chain reaction. Results: The combination of bezafibrate plus anti-PD-L1 reached synergistic tumoricidal effect in LLC xenograft mouse models, even though bezafibrate alone had no effect on tumor growth. Bezafibrate significantly facilitated CD8+ T cells infiltrating into tumor tissues by enhancing the expression of CXCL9 and CXCL10 within tumors as well as the receptor CXCR3 in infiltrating CTLs. Activated CTLs within tumors were also significantly upregulated by bezafibrate. Further data demonstrated that bezafibrate treatment could maintain the survival and functional capacity of tumor-infiltrating CTLs. Moreover, cellular reactive oxygen species in infiltrating CTLs and fatty acid oxidation (FAO)–related genes (PGC-1α, Cpt1a, and LCAD) expression within tumors were significantly increased after treatment with bezafibrate. Conclusions: Bezafibrate synergized the tumoricidal effect of PD-1 blockade in hyporesponsive lung cancer by expansion of effector CTLs within tumor microenvironment. The potential mechanism may relate to the capacity of bezafibrate in regulating FAO of tumor-infiltrating CTLs.

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Abstract P281: A Novel Mutation in Adiponectin Receptor 1 Contributes to Cardiac Hypertrophy and Cardiometabolic Dysregulation

Circulation ◽

10.1161/circ.129.suppl_1.p281 ◽

2014 ◽

Vol 129 (suppl_1) ◽

Author(s):

Soojeong Kang ◽

Perundurai S. Dhandapany ◽

Sreejith Kunnoth ◽

Uthiralingam Muthusami ◽

Kumarasamy Thangaraj ◽

...

Keyword(s):

Fatty Acid ◽

Glucose Uptake ◽

Novel Mutation ◽

Serine Phosphorylation ◽

Cardiomyocyte Hypertrophy ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Wild Type ◽

Gene Markers

Adiponectin, an adipocyte-derived cytokine, is known to influence cardiac remodeling and to suppress pathological cardiac growth and diabetes-induced disorders. Disruption of adiponectin or its receptor AdipoR1 has significant effects on cardiomyocyte hypertrophy and myocardial metabolism signal transduction. We recently identified a novel mutation in the AdipoR1 gene among 126 hypertrophic cardiomyopathy patients, including two family members with diabetes. Our screening identified a G>A transition at 146th position that replaced the amino acid valine (GUG) into methionine (AUG) (V146M). The consequences of this mutation on cardiac function and metabolism are not known. Here, using adenoviral gene delivery system, we found that Ad.V146M increased cell size, protein synthesis, induced expression of hypertrophic gene markers and increased serine phosphorylation of insulin receptor substrate 1 (IRS1) compared to control Ad.βGal or wild type AdipoR1 (Ad.AR1) in cultured cardiomyocytes. We also discovered that p38 and mTOR were activated by AdipoR1 mutant, but not wild-type. Pharmacological inhibition of p38 (SB203580) and mTOR (rapamycin) reversed the Ad.V146M-induced hypertrophic responses. Adiponectin is also known to promote the uptake and oxidation of fatty acid and glucose through AR1 in cultured myocytes. Recent studies suggest that p38 acts as an essential mediator in regulating adiponectin-induced glucose uptake and fatty acid oxidation in C2C12 myocytes, and the serine phosphorylation of IRS1 at S636/639 is known to be mediated by mTOR pathway. AdipoR1 mutant significantly deceased glucose uptake, facilitated palmitate uptake and repressed insulin responses. Interestingly, inhibition of p38 and mTOR pathways significantly attenuated the effects of Ad.V146M on the expression of genes involved in lipid oxidation (peroxisome proliferator-activated receptor α, PPARα; carnitine palmitoyltransferase 1, CPT1) or glucose utilization (phosphofructokinase, muscle, PFK-M), respectively. Intriguingly, these findings were confirmed in vivo in cardiac-specific transgenic mice overexpressing AdipoR1 mutant. Taken together, these results suggest that a mutation in the AdipoR1 may contribute to the development of cardiomyopathy via alterations in mTOR/p38 pathways and cardiac metabolism.

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