A small-molecule benzimidazole derivative that potently activates AMPK to increase glucose transport in skeletal muscle: comparison with effects of contraction and other AMPK activators

2014 ◽  
Vol 460 (3) ◽  
pp. 363-375 ◽  
Author(s):  
Yu-Chiang Lai ◽  
Samanta Kviklyte ◽  
Didier Vertommen ◽  
Louise Lantier ◽  
Marc Foretz ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Fatty Acid Oxidation ◽  
Small Molecule ◽  
Benzimidazole Derivative ◽  
Acid Oxidation

Study of a small-molecule AMPK activator that efficiently activates AMPK and stimulates glucose uptake and fatty acid oxidation in skeletal muscle.

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

2018 ◽  
Vol 46 (1) ◽  
pp. 187-202 ◽  
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.

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

1997 ◽  
Vol 273 (6) ◽  
pp. E1107-E1112 ◽  
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.

scholarly journals 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 ◽  
2019 ◽  
Vol 10 (6) ◽  
pp. 406 ◽  
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.

scholarly journals Ca 2+ effects on glucose transport and fatty acid oxidation in L6 skeletal muscle cell cultures

2016 ◽  
Vol 5 ◽  
pp. 365-373 ◽  
Author(s):  
Darrick Balu ◽  
Jiangyong Ouyang ◽  
Rahulkumar A. Parakhia ◽  
Saumitra Pitake ◽  
Raymond S. Ochs
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Transport ◽  
Fatty Acid Oxidation ◽  
Muscle Cell ◽  
Cell Cultures ◽  
Skeletal Muscle Cell ◽  
Acid Oxidation ◽  
L6 Skeletal Muscle Cell

Thujone, a component of medicinal herbs, rescues palmitate-induced insulin resistance in skeletal muscle

2010 ◽  
Vol 299 (3) ◽  
pp. R804-R812 ◽  
Author(s):  
Hakam Alkhateeb ◽  
Arend Bonen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Transport ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Glut4 Translocation ◽  
Palmitate Oxidation ◽  
Compound C ◽  
Ampk Phosphorylation

Thujone is thought to be the main constituent of medicinal herbs that have antidiabetic properties. Therefore, we examined whether thujone ameliorated palmitate-induced insulin resistance in skeletal muscle. Soleus muscles were incubated for ≤12 h without or with palmitate (2 mM). Thujone (0.01 mg/ml), in the presence of palmitate, was provided in the last 6 h of incubation. Palmitate oxidation, AMPK/acetyl-CoA carboxylase (ACC) phosphorylation and insulin-stimulated glucose transport, plasmalemmal GLUT4, and AS160 phosphorylation were examined at 0, 6, and 12 h. Palmitate treatment for 12 h reduced fatty acid oxidation (−47%), and insulin-stimulated glucose transport (−71%), GLUT4 translocation (−40%), and AS160 phosphorylation (−26%), but it increased AMPK (+51%) and ACC phosphorylations (+44%). Thujone (6–12 h) fully rescued palmitate oxidation and insulin-stimulated glucose transport, but only partially restored GLUT4 translocation and AS160 phosphorylation, raising the possibility that an increased GLUT4 intrinsic activity may also have contributed to the restoration of glucose transport. Thujone also further increased AMPK phosphorylation but had no further effect on ACC phosphorylation. Inhibition of AMPK phosphorylation with adenine 9-β-d-arabinofuranoside (Ara) (2.5 mM) or compound C (50 μM) inhibited the thujone-induced improvement in insulin-stimulated glucose transport, GLUT4 translocation, and AS160 phosphorylation. In contrast, the thujone-induced improvement in palmitate oxidation was only slightly inhibited (≤20%) by Ara or compound C. Thus, while thujone, a medicinal herb component, rescues palmitate-induced insulin resistance in muscle, the improvement in fatty acid oxidation cannot account for this thujone-mediated effect. Instead, the rescue of palmitate-induced insulin resistance appears to occur via an AMPK-dependent mechanism involving partial restoration of insulin-stimulated GLUT4 translocation.

α2-AMPK activity is not essential for an increase in fatty acid oxidation during low-intensity exercise

2009 ◽  
Vol 296 (1) ◽  
pp. E47-E55 ◽  
Author(s):  
Shinji Miura ◽  
Yuko Kai ◽  
Yasutomi Kamei ◽  
Clinton R. Bruce ◽  
Naoto Kubota ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Treadmill Exercise ◽  
Treadmill Running ◽  
Acid Oxidation ◽  
Low Intensity ◽  
Ampk Activity ◽  
Low Intensity Exercise

A single bout of exercise increases glucose uptake and fatty acid oxidation in skeletal muscle, with a corresponding activation of AMP-activated protein kinase (AMPK). While the exercise-induced increase in glucose uptake is partly due to activation of AMPK, it is unclear whether the increase of fatty acid oxidation is dependent on activation of AMPK. To examine this, transgenic mice were produced expressing a dominant-negative (DN) mutant of α1-AMPK (α1-AMPK-DN) in skeletal muscle and subjected to treadmill running. α1-AMPK-DN mice exhibited a 50% reduction in α1-AMPK activity and almost complete loss of α2-AMPK activity in skeletal muscle compared with wild-type littermates (WT). The fasting-induced decrease in respiratory quotient (RQ) ratio and reduced body weight were similar in both groups. In contrast with WT mice, α1-AMPK-DN mice could not perform high-intensity (30 m/min) treadmill exercise, although their response to low-intensity (10 m/min) treadmill exercise was not compromised. Changes in oxygen consumption and the RQ ratio during sedentary and low-intensity exercise were not different between α1-AMPK-DN and WT. Importantly, at low-intensity exercise, increased fatty acid oxidation in response to exercise in soleus (type I, slow twitch muscle) or extensor digitorum longus muscle (type II, fast twitch muscle) was not impaired in α1-AMPK-DN mice, indicating that α1-AMPK-DN mice utilize fatty acid in the same manner as WT mice during low-intensity exercise. These findings suggest that an increased α2-AMPK activity is not essential for increased skeletal muscle fatty acid oxidation during endurance exercise.

TBC1D1 reduces palmitate oxidation by inhibiting β-HAD activity in skeletal muscle

2014 ◽  
Vol 307 (9) ◽  
pp. R1115-R1123 ◽  
Author(s):  
A. C. Maher ◽  
J. McFarlan ◽  
J. Lally ◽  
L. A. Snook ◽  
A. Bonen
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Transport ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Rab Gtpase ◽  
Fatty Acid Transport ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Palmitate Oxidation ◽  
Mitochondrial Fatty Acid

In skeletal muscle the Rab-GTPase-activating protein TBC1D1 has been implicated in the regulation of fatty acid oxidation by an unknown mechanism. We determined whether TBC1D1 altered fatty acid utilization via changes in protein-mediated fatty acid transport and/or selected enzymes regulating mitochondrial fatty acid oxidation. We also determined the effects of TBC1D1 on glucose transport and oxidation. Electrotransfection of mouse soleus muscles with TBC1D1 cDNA increased TBC1D1 protein after 2 wk ( P < 0.05), without altering its paralog AS160. TBC1D1 overexpression decreased basal palmitate oxidation (−22%) while blunting 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)-stimulated palmitate oxidation (−18%). There was a tendency to increase fatty acid esterification (+10 nmol·g−1·60 min−1, P = 0.07), which reflected the reduction in fatty acid oxidation (−12 nmol·g−1·60 min−1). Concomitantly, basal (+21%) and AICAR-stimulated glucose oxidation (+8%) were increased in TBC1D1-transfected muscles relative to their respective controls ( P < 0.05), independent of changes in GLUT4 and glucose transport. The reductions in TBC1D1-mediated fatty acid oxidation could not be attributed to changes in the transporter FAT/CD36, muscle mitochondrial content, CPT1 expression or the expression and phosphorylation of AS160, acetyl-CoA carboxylase, or AMPK. However, TBC1D1 overexpression reduced β-HAD enzyme activity (−18%, P < 0.05). In conclusion, TBC1D1-mediated reduction of muscle fatty acid oxidation appears to occur via inhibition of β-HAD activity.

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