The Stimulatory Effect of Globular Adiponectin on Insulin-Stimulated Glucose Uptake and Fatty Acid Oxidation Is Impaired in Skeletal Muscle From Obese Subjects

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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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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The Suppressor of Cytokine Signaling 3 Inhibits Leptin Activation of AMP-Kinase in Cultured Skeletal Muscle of Obese Humans

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-0638 ◽

2006 ◽

Vol 91 (9) ◽

pp. 3592-3597 ◽

Cited By ~ 75

Author(s):

Gregory R. Steinberg ◽

Andrew J. McAinch ◽

Michael B. Chen ◽

Paul E. O’Brien ◽

John B. Dixon ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Acid Metabolism ◽

Leptin Resistance ◽

Cytokine Signaling ◽

Acid Oxidation ◽

Amp Kinase ◽

Ampk Signaling ◽

Obese Subjects

Abstract Context: Leptin is thought to regulate whole-body adiposity and insulin sensitivity, at least in part, by stimulating fatty acid metabolism via activation of AMP-kinase (AMPK) in skeletal muscle. Human obesity is associated with leptin resistance, and recent studies have demonstrated that hypothalamic expression of the suppressors of cytokine signaling 3 (SOCS3) regulates leptin sensitivity in rodents. Objective: The objective of the study was to investigate the effects of leptin on fatty acid oxidation and AMPK signaling in primary myotubes derived from lean and obese skeletal muscle and evaluate the contribution of SOCS3 to leptin resistance and AMPK signaling in obese humans. Results: We demonstrate that leptin stimulates AMPK activity and increases AMPK Thr172 and acetyl-CoA carboxylase-β Ser222 phosphorylation and fatty acid oxidation in lean myotubes but that in obese subjects leptin-dependent AMPK signaling and fatty acid oxidation are suppressed. Reduced activation of AMPK was associated with elevated expression of IL-6 (∼3.5-fold) and SOCS3 mRNA (∼2.5-fold) in myotubes of obese subjects. Overexpression of SOCS3 via adenovirus-mediated infection in lean myotubes to a similar degree as observed in obese myotubes prevented leptin but not AICAR (5-amino-imidazole-4-carboxamide-1-β-d-ribofuranoside) activation of AMPK signaling. Conclusions: These data demonstrate that SOCS3 inhibits leptin activation of AMPK. These data suggest that this impairment of leptin signaling in skeletal muscle may contribute to the aberrant regulation of fatty acid metabolism observed in obesity and that pharmacological activation of AMPK may be an effective therapy to bypass SOCS3-mediated skeletal muscle leptin resistance for the treatment of obesity-related disorders.

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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

Biochemical Journal ◽

10.1042/bj20131673 ◽

2014 ◽

Vol 460 (3) ◽

pp. 363-375 ◽

Cited By ~ 44

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.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90690.2008 ◽

2009 ◽

Vol 296 (1) ◽

pp. E47-E55 ◽

Cited By ~ 36

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.

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