Exogenous long chain C14 ceramide prevents insulin‐stimulated glucose uptake in C2C12 muscle cells independent of Akt signaling

Excessive fat accumulation has been considered as a major contributing factor for muscle mitochondrial dysfunction and its associated metabolic complications. The purpose of present study is to investigate a role of vitamin D in muscle fat accumulation and mitochondrial changes. In differentiated C2C12 muscle cells, palmitic acid (PA) was pretreated, followed by incubation with 1,25-dihyroxyvitamin D (1,25(OH)2D) for 24 h. PA led to a significant increment of triglyceride (TG) levels with increased lipid peroxidation and cellular damage, which were reversed by 1,25(OH)2D. The supplementation of 1,25(OH)2D significantly enhanced PA-decreased mtDNA levels as well as mRNA levels involved in mitochondrial biogenesis such as nuclear respiratory factor 1 (NRF1), peroxisome proliferative activated receptor gamma coactivator-1α (PGC-1α), and mitochondrial transcription factor A (Tfam) in C2C12 myotubes. Additionally, 1,25(OH)2D significantly increased ATP levels and gene expression related to mitochondrial function such as carnitine palmitoyltransferase 1 (CPT1), peroxisome proliferator-activated receptor α (PPARα), very long-chain acyl-CoA dehydrogenase (VLCAD), long-chain acyl-CoA dehydrogenase (LCAD), medium-chain acyl-CoA dehydrogenase (MCAD), uncoupling protein 2 (UCP2), and UCP3 and the vitamin D pathway including 25-dihydroxyvitamin D3 24-hydroxylase (CYP24) and 25-hydroxyvitamin D3 1-alpha-hydroxylase (CYP27) in PA-treated C2C12 myotubes. In addition to significant increment of sirtuin 1 (SIRT1) mRNA expression, increased activation of adenosine monophosphate-activated protein kinase (AMPK) and SIRT1 was found in 1,25(OH)2D-treated C2C12 muscle cells. Thus, we suggest that the observed protective effect of vitamin D on muscle fat accumulation and mitochondrial dysfunction in a positive manner via modulating AMPK/SIRT1 activation.

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Phloridzin Acts as an Inhibitor of Protein-Tyrosine Phosphatase MEG2 Relevant to Insulin Resistance

Molecules ◽

10.3390/molecules26061612 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1612

Author(s):

Sun-Young Yoon ◽

Jae Sik Yu ◽

Ji Young Hwang ◽

Hae Min So ◽

Seung Oh Seo ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Muscle Cells ◽

Protein Tyrosine ◽

C2c12 Muscle Cells

Inhibition of the megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2, also named PTPN9) activity has been shown to be a potential therapeutic strategy for the treatment of type 2 diabetes. Previously, we reported that PTP-MEG2 knockdown enhances adenosine monophosphate activated protein kinase (AMPK) phosphorylation, suggesting that PTP-MEG2 may be a potential antidiabetic target. In this study, we found that phloridzin, isolated from Ulmus davidiana var. japonica, inhibits the catalytic activity of PTP-MEG2 (half-inhibitory concentration, IC50 = 32 ± 1.06 μM) in vitro, indicating that it could be a potential antidiabetic drug candidate. Importantly, phloridzin stimulated glucose uptake by differentiated 3T3-L1 adipocytes and C2C12 muscle cells compared to that by the control cells. Moreover, phloridzin led to the enhanced phosphorylation of AMPK and Akt relevant to increased insulin sensitivity. Importantly, phloridzin attenuated palmitate-induced insulin resistance in C2C12 muscle cells. We also found that phloridzin did not accelerate adipocyte differentiation, suggesting that phloridzin improves insulin sensitivity without significant lipid accumulation. Taken together, our results demonstrate that phloridzin, an inhibitor of PTP-MEG2, stimulates glucose uptake through the activation of both AMPK and Akt signaling pathways. These results strongly suggest that phloridzin could be used as a potential therapeutic candidate for the treatment of type 2 diabetes.

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Magnesium Rich Extract of Cashew Tree (Anacardium Occidentale) Nut and its Principal Compound, Anacardic Acid, Stimulate Glucose Uptake in C2C12 Muscle Cells

International Journal of Complementary & Alternative Medicine ◽

10.15406/ijcam.2015.01.00010 ◽

2015 ◽

Vol 1 (2) ◽

Author(s):

Andrea Rosanoff

Keyword(s):

Glucose Uptake ◽

Muscle Cells ◽

Anacardium Occidentale ◽

Anacardic Acid ◽

C2c12 Muscle Cells ◽

Cashew Tree

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Leptin stimulates glucose uptake in C2C12 muscle cells by activation of ERK2

Molecular and Cellular Endocrinology ◽

10.1016/s0303-7207(99)00154-9 ◽

1999 ◽

Vol 157 (1-2) ◽

pp. 121-130 ◽

Cited By ~ 54

Author(s):

Lucia Berti ◽

Steen Gammeltoft

Keyword(s):

Glucose Uptake ◽

Muscle Cells ◽

C2c12 Muscle Cells

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Bis-Indole–Derived NR4A1 Ligands and Metformin Exhibit NR4A1-Dependent Glucose Metabolism and Uptake in C2C12 Cells

Endocrinology ◽

10.1210/en.2017-03049 ◽

2018 ◽

Vol 159 (5) ◽

pp. 1950-1963 ◽

Cited By ~ 5

Author(s):

Kumaravel Mohankumar ◽

Jehoon Lee ◽

Chia Shan Wu ◽

Yuxiang Sun ◽

Stephen Safe

Keyword(s):

Glucose Metabolism ◽

Cell Membrane ◽

Protein Expression ◽

Glucose Uptake ◽

Messenger Rna ◽

Muscle Cells ◽

C2c12 Cells ◽

Gene And Protein Expression ◽

C2c12 Muscle Cells

Abstract Treatment of C2C12 muscle cells with metformin or the NR4A1 ligand 1,1-bis(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) induced NR4A1 and Glut4 messenger RNA and protein expression. Similar results were observed with buttressed (3- or 3,5-substituted) analogs of DIM-C-pPhOH, including 1,1-bis(3′-indolyl)-1-(3-chloro-4-hydroxy-5-methoxyphenyl)methane (DIM-C-pPhOH-3-Cl-5-OCH3), and the buttressed analogs were more potent than DIM-C-pPhOH NR4A1 agonists. Metformin and the bis-indole substituted analogs also induced expression of several glycolytic genes and Rab4, which has previously been linked to enhancing cell membrane accumulation of Glut4 and overall glucose uptake in C2C12 cells, and these responses were also observed after treatment with metformin and the NR4A1 ligands. The role of NR4A1 in mediating the responses induced by the bis-indoles and metformin was determined by knockdown of NR4A1, and this resulted in attenuating the gene and protein expression and enhanced glucose uptake responses induced by these compounds. Our results demonstrate that the bis-indole–derived NR4A1 ligands represent a class of drugs that enhance glucose uptake in C2C12 muscle cells, and we also show that the effects of metformin in this cell line are NR4A1-dependent.

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