α2 Isoform–specific activation of 5′adenosine monophosphate–activated protein kinase by 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside at a physiological level activates glucose transport and increases glucose transporter 4 in mouse skeletal muscle

The objective of this study was to evaluate the antihyperlipidemic and antihyperglycemic effects and mechanism of the extract ofClitocybe nuda(CNE), in high-fat- (HF-) fed mice. C57BL/6J was randomly divided into two groups: the control (CON) group was fed with a low-fat diet, whereas the experimental group was fed with a HF diet for 8 weeks. Then, the HF group was subdivided into five groups and was given orally CNE (including C1: 0.2, C2: 0.5, and C3: 1.0 g/kg/day extracts) or rosiglitazone (Rosi) or vehicle for 4 weeks. CNE effectively prevented HF-diet-induced increases in the levels of blood glucose, triglyceride, insulin (P<0.001,P<0.01,P<0.05, resp.) and attenuated insulin resistance. By treatment with CNE, body weight gain, weights of white adipose tissue (WAT) and hepatic triacylglycerol content were reduced; moreover, adipocytes in the visceral depots showed a reduction in size. By treatment with CNE, the protein contents of glucose transporter 4 (GLUT4) were significantly increased in C3-treated group in the skeletal muscle. Furthermore, CNE reduces the hepatic expression of glucose-6-phosphatase (G6Pase) and glucose production. CNE significantly increases protein contents of phospho-AMP-activated protein kinase (AMPK) in the skeletal muscle and adipose and liver tissues. Therefore, it is possible that the activation of AMPK by CNE leads to diminished gluconeogenesis in the liver and enhanced glucose uptake in skeletal muscle. It is shown that CNE exhibits hypolipidemic effect in HF-fed mice by increasing ATGL expression, which is known to help triglyceride to hydrolyze. Moreover, antidiabetic properties of CNE occurred as a result of decreased hepatic glucose production via G6Pase downregulation and improved insulin sensitization. Thus, amelioration of diabetic and dyslipidemic states by CNE in HF-fed mice occurred by regulation of GLUT4, G6Pase, ATGL, and AMPK phosphorylation.

Download Full-text

Overexpression of mitofusin 2 improves translocation of glucose transporter 4 in skeletal muscle of high-fat diet-fed rats through AMP-activated protein kinase signaling

Molecular Medicine Reports ◽

10.3892/mmr.2013.1457 ◽

2013 ◽

Vol 8 (1) ◽

pp. 205-210 ◽

Cited By ~ 16

Author(s):

DEXIAN KONG ◽

GUANGYAO SONG ◽

CHAO WANG ◽

HUIJUAN MA ◽

LUPING REN ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

High Fat Diet ◽

Glucose Transporter ◽

Kinase Signaling ◽

Glucose Transporter 4 ◽

High Fat ◽

Mitofusin 2 ◽

Amp Activated Protein Kinase ◽

Protein Kinase Signaling

Download Full-text

Roles of adenosine monophosphate–activated protein kinase in skeletal muscle: fatty acid oxidation, glucose transport, and gene regulation

Current Opinion in Endocrinology & Diabetes ◽

10.1097/00060793-200108000-00003 ◽

2001 ◽

Vol 8 (4) ◽

pp. 180-185 ◽

Cited By ~ 2

Author(s):

William W. Winder

Keyword(s):

Skeletal Muscle ◽

Gene Regulation ◽

Fatty Acid ◽

Protein Kinase ◽

Glucose Transport ◽

Fatty Acid Oxidation ◽

Adenosine Monophosphate ◽

Acid Oxidation

Download Full-text

Crucial role of the small GTPase Rac1 in insulin‐stimulated translocation of glucose transporter 4 to the mouse skeletal muscle sarcolemma

The FASEB Journal ◽

10.1096/fj.09-137380 ◽

2010 ◽

Vol 24 (7) ◽

pp. 2254-2261 ◽

Cited By ~ 80

Author(s):

Shuji Ueda ◽

Sohei Kitazawa ◽

Kota Ishida ◽

Yuki Nishikawa ◽

Megumi Matsui ◽

...

Keyword(s):

Skeletal Muscle ◽

Crucial Role ◽

Glucose Transporter ◽

Small Gtpase ◽

Glucose Transporter 4 ◽

Mouse Skeletal Muscle

Download Full-text

Activation of Protein Kinase Cζ Induces Serine Phosphorylation of VAMP2 in the GLUT4 Compartment and Increases Glucose Transport in Skeletal Muscle

Molecular and Cellular Biology ◽

10.1128/mcb.21.22.7852-7861.2001 ◽

2001 ◽

Vol 21 (22) ◽

pp. 7852-7861 ◽

Cited By ~ 66

Author(s):

Liora Braiman ◽

Addy Alt ◽

Toshio Kuroki ◽

Motoi Ohba ◽

Asia Bak ◽

...

Keyword(s):

Skeletal Muscle ◽

Plasma Membrane ◽

Protein Kinase ◽

Glucose Uptake ◽

Glucose Transport ◽

Glucose Transporter ◽

Primary Cultures ◽

Dominant Negative ◽

Serine Phosphorylation ◽

Glut4 Translocation

ABSTRACT Insulin stimulates glucose uptake into skeletal muscle tissue mainly through the translocation of glucose transporter 4 (GLUT4) to the plasma membrane. The precise mechanism involved in this process is presently unknown. In the cascade of events leading to insulin-induced glucose transport, insulin activates specific protein kinase C (PKC) isoforms. In this study we investigated the roles of PKCζ in insulin-stimulated glucose uptake and GLUT4 translocation in primary cultures of rat skeletal muscle. We found that insulin initially caused PKCζ to associate specifically with the GLUT4 compartments and that PKCζ together with the GLUT4 compartments were then translocated to the plasma membrane as a complex. PKCζ and GLUT4 recycled independently of one another. To further establish the importance of PKCζ in glucose transport, we used adenovirus constructs containing wild-type or kinase-inactive, dominant-negative PKCζ (DNPKCζ) cDNA to overexpress this isoform in skeletal muscle myotube cultures. We found that overexpression of PKCζ was associated with a marked increase in the activity of this isoform. The overexpressed, active PKCζ coprecipitated with the GLUT4 compartments. Moreover, overexpression of PKCζ caused GLUT4 translocation to the plasma membrane and increased glucose uptake in the absence of insulin. Finally, either insulin or overexpression of PKCζ induced serine phosphorylation of the GLUT4-compartment-associated vesicle-associated membrane protein 2. Furthermore, DNPKCζ disrupted the GLUT4 compartment integrity and abrogated insulin-induced GLUT4 translocation and glucose uptake. These results demonstrate that PKCζ regulates insulin-stimulated GLUT4 translocation and glucose transport through the unique colocalization of this isoform with the GLUT4 compartments.

Download Full-text

CaMKII regulates contraction- but not insulin-induced glucose uptake in mouse skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00659.2009 ◽

2010 ◽

Vol 298 (6) ◽

pp. E1150-E1160 ◽

Cited By ~ 56

Author(s):

Carol A. Witczak ◽

Niels Jessen ◽

Daniel M. Warro ◽

Taro Toyoda ◽

Nobuharu Fujii ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Glucose Uptake ◽

Intracellular Signaling ◽

Glucose Transporter ◽

Fluorescent Protein ◽

Critical Role ◽

Expression Vectors ◽

Inhibitory Peptide ◽

Mouse Skeletal Muscle

Studies using chemical inhibitors have suggested that the Ca2+-sensitive serine/threonine kinase Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key regulator of both insulin- and contraction-stimulated glucose uptake in skeletal muscle. However, due to nonspecificity of these inhibitors, the specific role that CaMKII may play in the regulation of glucose uptake is not known. We sought to determine whether specific inhibition of CaMKII impairs insulin- and/or contraction-induced glucose uptake in mouse skeletal muscle. Expression vectors containing green fluorescent protein conjugated to a CaMKII inhibitory (KKALHRQEAVDCL) or control (KKALHAQERVDCL) peptide were transfected into tibialis anterior muscles by in vivo electroporation. After 1 wk, muscles were assessed for peptide expression, CaMK activity, insulin- and contraction-induced 2-[3H]deoxyglucose uptake, glycogen concentrations, and changes in intracellular signaling proteins. Expression of the CaMKII inhibitory peptide decreased muscle CaMK activity ∼35% compared with control peptide. Insulin-induced glucose uptake was not changed in muscles expressing the inhibitory peptide. In contrast, expression of the inhibitory peptide significantly decreased contraction-induced muscle glucose uptake (∼30%). Contraction-induced decreases in muscle glycogen were not altered by the inhibitory peptide. The CaMKII inhibitory peptide did not alter expression of the glucose transporter GLUT4 and did not impair contraction-induced increases in the phosphorylation of AMP-activated protein kinase (Thr172) or TBC1D1/TBC1D4 on phospho-Akt substrate sites. These results demonstrate that CaMKII does not regulate insulin-stimulated glucose uptake in skeletal muscle. However, CaMKII plays a critical role in the regulation of contraction-induced glucose uptake in mouse skeletal muscle.

Download Full-text

Exercise signalling to glucose transport in skeletal muscle

Proceedings of The Nutrition Society ◽

10.1079/pns2004343 ◽

2004 ◽

Vol 63 (2) ◽

pp. 211-216 ◽

Cited By ~ 35

Author(s):

Erik A. Richter ◽

Jakob N. Nielsen ◽

Sebastian B. Jørgensen ◽

Christian Frøsig ◽

Jesper B. Birk ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Glucose Uptake ◽

Glucose Transport ◽

Glucose Transporter ◽

Surface Membrane ◽

Mitogen Activated Protein Kinase ◽

Storage Site ◽

Mitogen Activated Protein ◽

Intracellular Storage

Contraction-induced glucose uptake in skeletal muscle is mediated by an insulin-independent mechanism that leads to translocation of the GLUT4 glucose transporter to the muscle surface membrane from an intracellular storage site. Although the signalling events that increase glucose transport in response to muscle contraction are not fully elucidated, the aim of the present review is to briefly present the current understanding of the molecular signalling mechanisms involved. Glucose uptake may be regulated by Ca2+-sensitive contraction-related mechanisms, possibly involving Ca2+/calmodulin-dependent protein kinase II and some isoforms of protein kinase C. In addition, glucose transport may be regulated by mechanisms that reflect the metabolic status of the muscle, probably involving the 5′AMP-activated protein kinase. Furthermore, the p38 mitogen-activated protein kinase may be involved in activating the GLUT4 translocated to the surface membrane. Nevertheless, the picture is incomplete, and fibre type differences also seem to be involved.

Download Full-text