Exercise signalling to glucose transport in skeletal muscle

Richter, Erik A.; Nielsen, Jakob N.; Jørgensen, Sebastian Beck; Frank, Christian; Birk, Jesper B.

doi:10.1079/pns2004343

Cited by 46 publications

(37 citation statements)

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“…Because p38 has been shown to play a stimulatory role in glucose uptake in skeletal muscles and adipocytes through expression of Glut4 (41)(42)(43)(44)(45)(46)(47)(48)(49), the blockade of p38 may reduce glucose uptake in theses tissues, resulting in excess glucose supply. The excess glucose is then converted into fatty acids and contributes to the development of hypertriglyceridemia and fatty liver.…”

Section: Discussionmentioning

confidence: 99%

p38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis

Xiong

Collins

et al. 2007

Journal of Biological Chemistry

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Hepatic lipogenesis is the principal route to convert excess carbohydrates into fatty acids and is mainly regulated by two opposing hormones, insulin and glucagon. Although insulin stimulates hepatic lipogenesis, glucagon inhibits it. However, the mechanism by which glucagon suppresses lipogenesis remains poorly understood. In this study, we have observed that p38 mitogen-activated protein kinase plays an inhibitory role in hepatic lipogenesis. Levels of plasma triglyceride and triglyceride accumulation in the liver were both elevated when p38 activation was blocked. Expression levels of central lipogenic genes, including sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase, hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl pyrophosphate synthase, and cytochrome P-450-51, were decreased in liver by fasting and in primary hepatocytes by glucagon but increased by the inhibition of p38. In addition, we have shown that p38 can inhibit insulin-induced expression of key lipogenic genes in isolated hepatocytes. Our results in hepatoma cells demonstrate that p38 plays an inhibitory role in the activation of the SREBP-1c promoter. Finally, we have shown that transcription of the PGC-1␤ gene, a key coactivator of SREBP-1c, was reduced in liver by fasting and in isolated hepatocytes by glucagon. This reduction was significantly reversed by the blockade of p38. Insulin-induced expression of the PGC-1␤ gene was enhanced by the inhibition of p38 but suppressed by the activation of p38. Together, we have identified an inhibitory role for p38 in the transcription of central lipogenic genes, SREBPs, and PGC-1␤ and hepatic lipogenesis.Hepatic lipogenesis is essential for maintaining energy balance (1). Disorders of hepatic lipogenesis may lead to fatty liver, dyslipidemia, type II diabetes mellitus, and complications such as atherosclerosis (2). Lipogenesis in liver includes de novo synthesis of fatty acids and cholesterols. As a major site for synthesis of fatty acids, the liver converts excess carbohydrates into fat storage in the fed state. Fatty acids synthesized in the liver are converted into triglycerides and secreted as very low density lipoproteins, which transport fatty acids to the storage sites in adipocytes. Cholesterols synthesized in the liver are also transported to other tissues via very low density lipoproteins as essential building materials for steroid hormones and cellular membranes. However, excess production of fatty acids and cholesterols from the liver may contribute to a variety of lipid disorders. The lipogenic process in the liver is primarily regulated by central lipogenic transcription factors, sterol regulatory element-binding proteins (SREBPs) 2 (reviewed in Refs. 3 and 4).The SREBPs are basic helix-loop-helix-leucine zipper-containing transcription factors (5). Among three known SREBPs, SREBP-1a and -1c are encoded by the same gene; SREBP-1c lacks the N-terminal exon compared with SREBP-1a (6). SREBP-2 is encoded by a separate gene (7). Although SREBPs share similar lip...

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Section: Discussionmentioning

confidence: 99%

p38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis

Xiong

Collins

et al. 2007

Journal of Biological Chemistry

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“…In addition, the combination of AICAR and insulin promoted an additional glucose transport in muscle and neuronal cells (Shah et al 2011, Fediuc et al 2006, Hayashi et al 1998. However, the effect of AICAR on glucose uptake is lost when α2 or γ3 AMPK subunits are deficient (Barnes et al 2004, Jorgensen et al 2004, Mu et al 2001.…”

Section: Amp-activated Protein Kinase (Ampk)mentioning

confidence: 99%

“…Jorgensen et al 2004, studying soleus and EDL muscles of mice, showed that muscles of α1 or α2-AMPK knockout (KO) mice when stimulated by muscle contraction, present glucose uptake similar to wild-type mice. However, when stimulated by AICAR, only muscles of α1-AMPK KO mice showed glucose uptake levels preserved.…”

Section: Glucose Uptake Pathwaysmentioning

confidence: 99%

General aspects of muscle glucose uptake

Alvim

Cheuhen

Machado

et al. 2015

An. Acad. Bras. Ciênc.

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Glucose uptake in peripheral tissues is dependent on the translocation of GLUT4 glucose transporters to the plasma membrane. Studies have shown the existence of two major signaling pathways that lead to the translocation of GLUT4. The first, and widely investigated, is the insulin activated signaling pathway through insulin receptor substrate-1 and phosphatidylinositol 3-kinase. The second is the insulin-independent signaling pathway, which is activated by contractions. Individuals with type 2 diabetes mellitus have reduced insulin-stimulated glucose uptake in skeletal muscle due to the phenomenon of insulin resistance. However, those individuals have normal glucose uptake during exercise. In this context, physical exercise is one of the most important interventions that stimulates glucose uptake by insulin-independent pathways, and the main molecules involved are adenosine monophosphate-activated protein kinase, nitric oxide, bradykinin, AKT, reactive oxygen species and calcium. In this review, our main aims were to highlight the different glucose uptake pathways and to report the effects of physical exercise, diet and drugs on their functioning. Lastly, with the better understanding of these pathways, it would be possible to assess, exactly and molecularly, the importance of physical exercise and diet on glucose homeostasis. Furthermore, it would be possible to assess the action of drugs that might optimize glucose uptake and consequently be an important step in controlling the blood glucose levels in diabetic patients, in addition to being important to clarify some pathways that justify the development of drugs capable of mimicking the contraction pathway.

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“…Together these second messengers activate a complex network of signaling events (353). Among all the protein kinases activated by contraction [e.g., PKA, PKC-␦ and -, extracellularly regulated protein kinases (ERK)-1 and -2, mitogen-activated protein kinase (MAPK), and Ca 2ϩ /calmodulin-dependent protein kinases (CaMK)], the activation of AMPactivated protein kinase (AMPK) is known to have a variety of metabolic actions (275,352), including the stimulation of fatty acid oxidation via the phosphorylation and inactivation of acyl-CoA carboxylase (ACC) and the consequent reduction in malonyl-CoA which releases the inhibitory effects on CPT-I (270, 400). In line with this, we have shown that AMPK plays a crucial role in the translocation of CD36 (73,277), and that of FABP pm (73).…”

Section: Contraction Signalingmentioning

confidence: 99%

Membrane Fatty Acid Transporters as Regulators of Lipid Metabolism: Implications for Metabolic Disease

Glatz

Luiken

Bonen

2010

Physiological Reviews

616

662

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Long-chain fatty acids and lipids serve a wide variety of functions in mammalian homeostasis, particularly in the formation and dynamic properties of biological membranes and as fuels for energy production in tissues such as heart and skeletal muscle. On the other hand, long-chain fatty acid metabolites may exert toxic effects on cellular functions and cause cell injury. Therefore, fatty acid uptake into the cell and intracellular handling need to be carefully controlled. In the last few years, our knowledge of the regulation of cellular fatty acid uptake has dramatically increased. Notably, fatty acid uptake was found to occur by a mechanism that resembles that of cellular glucose uptake. Thus, following an acute stimulus, particularly insulin or muscle contraction, specific fatty acid transporters translocate from intracellular stores to the plasma membrane to facilitate fatty acid uptake, just as these same stimuli recruit glucose transporters to increase glucose uptake. This regulatory mechanism is important to clear lipids from the circulation postprandially and to rapidly facilitate substrate provision when the metabolic demands of heart and muscle are increased by contractile activity. Studies in both humans and animal models have implicated fatty acid transporters in the pathogenesis of diseases such as the progression of obesity to insulin resistance and type 2 diabetes. As a result, membrane fatty acid transporters are now being regarded as a promising therapeutic target to redirect lipid fluxes in the body in an organ-specific fashion.

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Exercise signalling to glucose transport in skeletal muscle

Cited by 46 publications

References 41 publications

p38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis

p38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis

General aspects of muscle glucose uptake

Membrane Fatty Acid Transporters as Regulators of Lipid Metabolism: Implications for Metabolic Disease

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