Chronic exposure to palmitate impairs fatty acid oxidation and insulin‐stimulated glucose uptake despite activation of AMPK in skeletal muscle cells

Elevated plasma free fatty acids cause insulin resistance in skeletal muscle through the activation of a chronic inflammatory process. This process involves nuclear factor (NF)-κB activation as a result of diacylglycerol (DAG) accumulation and subsequent protein kinase Cθ (PKCθ) phosphorylation. At present, it is unknown whether peroxisome proliferator-activated receptor-δ (PPARδ) activation prevents fatty acid-induced inflammation and insulin resistance in skeletal muscle cells. In C2C12 skeletal muscle cells, the PPARδ agonist GW501516 prevented phosphorylation of insulin receptor substrate-1 at Ser307 and the inhibition of insulin-stimulated Akt phosphorylation caused by exposure to the saturated fatty acid palmitate. This latter effect was reversed by the PPARδ antagonist GSK0660. Treatment with the PPARδ agonist enhanced the expression of two well known PPARδ target genes involved in fatty acid oxidation, carnitine palmitoyltransferase-1 and pyruvate dehydrogenase kinase 4 and increased the phosphorylation of AMP-activated protein kinase, preventing the reduction in fatty acid oxidation caused by palmitate exposure. In agreement with these changes, GW501516 treatment reversed the increase in DAG and PKCθ activation caused by palmitate. These effects were abolished in the presence of the carnitine palmitoyltransferase-1 inhibitor etomoxir, thereby indicating that increased fatty acid oxidation was involved in the changes observed. Consistent with these findings, PPARδ activation by GW501516 blocked palmitate-induced NF-κB DNA-binding activity. Likewise, drug treatment inhibited the increase in IL-6 expression caused by palmitate in C2C12 and human skeletal muscle cells as well as the protein secretion of this cytokine. These findings indicate that PPARδ attenuates fatty acid-induced NF-κB activation and the subsequent development of insulin resistance in skeletal muscle cells by reducing DAG accumulation. Our results point to PPARδ activation as a pharmacological target to prevent insulin resistance.

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

Cellular Physiology and Biochemistry ◽

10.1159/000488422 ◽

2018 ◽

Vol 46 (1) ◽

pp. 187-202 ◽

Cited By ~ 15

Author(s):

Jaume Amengual ◽

Francisco J. García-Carrizo ◽

Andrea Arreguín ◽

Hana Mušinović ◽

Nuria Granados ◽

...

Keyword(s):

Skeletal Muscle ◽

Retinoic Acid ◽

Fatty Acid ◽

Glucose Uptake ◽

Fatty Acid Oxidation ◽

Kinase Inhibitor ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Protective Effects

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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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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