Fritah, A;
Steel, JH;
Parker, N;
Nikolopoulou, E;
Christian, M;
Carling, D;
Parker, MG;
(2012)
Absence of RIP140 Reveals a Pathway Regulating glut4-Dependent Glucose Uptake in Oxidative Skeletal Muscle through UCP1-Mediated Activation of AMPK.
PLOS ONE
, 7
(2)
, Article e32520. 10.1371/journal.pone.0032520.
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Abstract
Skeletal muscle constitutes the major site of glucose uptake leading to increased removal of glucose from the circulation in response to insulin. Type 2 diabetes and obesity are often associated with insulin resistance that can be counteracted by exercise or the use of drugs increasing the relative proportion of oxidative fibers. RIP140 is a transcriptional coregulator with a central role in metabolic tissues and we tested the effect of modulating its level of expression on muscle glucose and lipid metabolism in two mice models. Here, we show that although RIP140 protein is expressed at the same level in both oxidative and glycolytic muscles, it inhibits both fatty acid and glucose utilization in a fiber-type dependent manner. In RIP140-null mice, fatty acid utilization increases in the extensor digitorum longus and this is associated with elevated expression of genes implicated in fatty acid binding and transport. In the RIP140-null soleus, depletion of RIP140 leads to increased GLUT4 trafficking and glucose uptake with no change in Akt activity. AMPK phosphorylation/activity is inhibited in the soleus of RIP140 transgenic mice and increased in RIP140-null soleus. This is associated with increased UCP1 expression and mitochondrial uncoupling revealing the existence of a signaling pathway controlling insulin-independent glucose uptake in the soleus of RIP140-null mice. In conclusion, our findings reinforce the participation of RIP140 in the maintenance of energy homeostasis by acting as an inhibitor of energy production and particularly point to RIP140 as a promising therapeutic target in the treatment of insulin resistance.
| Type: | Article |
|---|---|
| Title: | Absence of RIP140 Reveals a Pathway Regulating glut4-Dependent Glucose Uptake in Oxidative Skeletal Muscle through UCP1-Mediated Activation of AMPK |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pone.0032520 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pone.0032520 |
| Language: | English |
| Additional information: | © 2012 Fritah et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This work was supported by grants from the Wellcome Trust, Reference 079200/Z/06/Z (AF and JHS). http://www.wellcome.ac.uk/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| UCL classification: | UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1383175 |
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