AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity in mice

Abstract Context Almost 50% of type 2 diabetic (T2D) patients are poorly controlled [glycated hemoglobin (HbA1c) ≥ 7%]; however, the mechanisms responsible for progressively worsening glycemic control are poorly understood. Lower skeletal muscle mitochondrial respiratory capacity is associated with low insulin sensitivity and the development of T2D. Objective We investigated if skeletal muscle insulin sensitivity (SI) was different between well-controlled T2D (WCD) and poorly controlled T2D (PCD) and if the difference was associated with differences resulting from mitochondrial respiratory function. Design Vastus lateralis muscle mitochondrial respiration, mitochondrial content, mitochondrial enzyme activity, and fatty acid oxidation (FAO) were measured. SI and the acute response to glucose (AIRg) were calculated by MINMOD analysis from glucose and insulin obtained during a modified, frequently sampled, intravenous glucose tolerance test. Results SI and AIRg were lower in PCD than WCD. Muscle incomplete FAO was greater in PCD than WCD and greater incomplete FAO was associated with lower SI and higher HbA1c. Hydroxyacyl-coenzyme A dehydrogenase expression and activity were greater in PCD than WCD. There was no difference in maximal mitochondrial respiration or content between WCD and PCD. Conclusion The current results suggest that greater skeletal muscle incomplete FAO in poorly controlled T2D is due to elevated β oxidation and is associated with worsening muscle SI.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00216.2010 ◽

2010 ◽

Vol 299 (3) ◽

pp. R804-R812 ◽

Cited By ~ 18

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.

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PGC-1α-induced improvements in skeletal muscle metabolism and insulin sensitivityThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

Applied Physiology Nutrition and Metabolism ◽

10.1139/h09-008 ◽

2009 ◽

Vol 34 (3) ◽

pp. 307-314 ◽

Cited By ~ 46

Author(s):

Arend Bonen

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Insulin Sensitivity ◽

Fatty Acid Oxidation ◽

Insulin Signalling ◽

Metabolic Effects ◽

Zucker Rats ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid ◽

Exercise Induced

The peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), a nuclear encoded transcriptional coactivator, increases the expression of many genes in skeletal muscle, including those involved with fatty acid oxidation and oxidative phosphorylation. Exercise increases the expression of PGC-1α, and the exercise-induced upregulation of many genes is attributable, in part, to the preceding activation and upregulation of PGC-1α. Indeed, PGC-1α overexpression, like exercise training, increases exercise performance. PGC-1α reductions in humans have been observed in type 2 diabetes, while, in cell lines, PGC-1α mimics the exercise-induced improvement in insulin sensitivity. However, unexpectedly, in mammalian muscle, PGC-1α overexpression contributed to the development of diet-induced insulin resistance. This may have been related to the massive overexpression of PGC-1α, which induced the upregulation of the fatty acid transporter FAT/CD36 and led to an increase in intramuscular lipids, which interfere with insulin signalling. In contrast, when PGC-1α was overexpressed modestly, within physiological limits, mitochondrial fatty acid oxidation was increased, GLUT4 expression was upregulated, and insulin-stimulated glucose transport was increased. More recently, similar PGC-1α-induced improvements in the insulin-resistant skeletal muscle of obese Zucker rats have been observed. These studies suggest that massive PGC-1α overexpression, but not physiologic PGC-1α overexpression, induces deleterious metabolic effects, and that exercise-induced improvements in insulin sensitivity are induced, in part, by the exercise-induced upregulation of PGC-1α.

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Carnitine-Palmitoyltransferase-1 Deficiency Impairs Skeletal Muscle Fatty Acid Oxidation, But Preserves Insulin Sensitivity

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2012.10.184 ◽

2012 ◽

Vol 53 ◽

pp. S99

Author(s):

Shawna E. Wicks ◽

Bolormaa Vandanmagsar ◽

Kimberly R. Haynie ◽

Jingying Zhang ◽

Robert Noland ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Insulin Sensitivity ◽

Fatty Acid Oxidation ◽

Carnitine Palmitoyltransferase ◽

Acid Oxidation ◽

Carnitine Palmitoyltransferase 1

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Genistein stimulates insulin sensitivity through gut microbiota reshaping and skeletal muscle AMPK activation in obese subjects

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000948 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000948 ◽

Cited By ~ 3

Author(s):

Martha Guevara-Cruz ◽

Einar T Godinez-Salas ◽

Monica Sanchez-Tapia ◽

Gonzalo Torres-Villalobos ◽

Edgar Pichardo-Ontiveros ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Fatty Acid ◽

Insulin Sensitivity ◽

Gut Microbiota ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Oral Glucose ◽

Model Assessment ◽

Metabolic Endotoxemia

ObjectiveObesity is associated with metabolic abnormalities, including insulin resistance and dyslipidemias. Previous studies demonstrated that genistein intake modifies the gut microbiota in mice by selectively increasing Akkermansia muciniphila, leading to reduction of metabolic endotoxemia and insulin sensitivity. However, it is not known whether the consumption of genistein in humans with obesity could modify the gut microbiota reducing the metabolic endotoxemia and insulin sensitivity.Research design and methods45 participants with a Homeostatic Model Assessment (HOMA) index greater than 2.5 and body mass indices of ≥30 and≤40 kg/m2 were studied. Patients were randomly distributed to consume (1) placebo treatment or (2) genistein capsules (50 mg/day) for 2 months. Blood samples were taken to evaluate glucose concentration, lipid profile and serum insulin. Insulin resistance was determined by means of the HOMA for insulin resistance (HOMA-IR) index and by an oral glucose tolerance test. After 2 months, the same variables were assessed including a serum metabolomic analysis, gut microbiota, and a skeletal muscle biopsy was obtained to study the gene expression of fatty acid oxidation.ResultsIn the present study, we show that the consumption of genistein for 2 months reduced insulin resistance in subjects with obesity, accompanied by a modification of the gut microbiota taxonomy, particularly by an increase in the Verrucomicrobia phylum. In addition, subjects showed a reduction in metabolic endotoxemia and an increase in 5′-adenosine monophosphate-activated protein kinase phosphorylation and expression of genes involved in fatty acid oxidation in skeletal muscle. As a result, there was an increase in circulating metabolites of β-oxidation and ω-oxidation, acyl-carnitines and ketone bodies.ConclusionsChange in the gut microbiota was accompanied by an improvement in insulin resistance and an increase in skeletal muscle fatty acid oxidation. Therefore, genistein could be used as a part of dietary strategies to control the abnormalities associated with obesity, particularly insulin resistance; however, long-term studies are needed.

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Skeletal muscle fatty acid oxidation is not directly associated with AMPK or ACC2 phosphorylation

Applied Physiology Nutrition and Metabolism ◽

10.1139/h11-024 ◽

2011 ◽

Vol 36 (3) ◽

pp. 361-367 ◽

Cited By ~ 8

Author(s):

Hakam Alkhateeb ◽

Graham P. Holloway ◽

Arend Bonen

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Palmitate Oxidation ◽

Compound C ◽

Ampk Phosphorylation ◽

Growing Body ◽

C 50

Rescue of palmitate-induced insulin resistance has been linked with improvements in fatty acid oxidation, but importantly, not always with concurrently altered AMPK or ACC2 phosphorylation. Therefore, we examined the interrelationships among AMPK, ACC2, and fatty acid oxidation under 12 controlled conditions in isolated muscle. Incubation of soleus muscle (0–12 h) did not alter fatty acid oxidation, but did increase AMPK and ACC2 phosphorylation (24%–30%). Muscle incubation with palmitate (2 mmol·L–1) inhibited palmitate oxidation (∼55%), but paradoxically, this was associated with increased AMPK and ACC2 phosphorylation (∼50%). Addition of an AMPK activator (thujone) to control (no palmitate) muscle increased AMPK and ACC2 phosphorylation (∼25%) but did not alter palmitate oxidation. Addition of AMPK inhibitors, compound C (50 µmol·L–1) or adenine 9-β-d-arabinofuranoside (Ara; 2.5 mmol·L–1), to thujone-treated muscles (no palmitate) did not alter palmiate oxidation but reduced AMPK phosphorylation (32%–42%), while ACC2 phosphorylation remained above basal level (+14%–18%). Finally, in palmitate-treated muscle, thujone increased AMPK (+100%) and ACC2 phosphorylation (+52%) and restored palmitate oxidation. Compound C or Ara, administered along with thujone in palmitate-treated muscle, only partly blunted palmitate oxidation recovery despite inhibiting AMPK phosphorylation (–22%), although ACC2 phosphorylation remained upregulated (+33%). Among these experiments, AMPK phosphorylation and ACC2 phosphorylation were positively correlated. However, AMPK phosphorylation was not correlated with palmitate oxidation, and unexpectedly, palmitate oxidation was negatively correlated with ACC2 phosphorylation. Our study, in accordance with a growing body of evidence, indicates that neither AMPK phosphorylation nor ACC2 phosphorylation is by itself an appropriate marker of fatty acid oxidation, and further serves to question their regulatory role.

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