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This version published online on January 27, 2005
Endocrinology, doi:10.1210/en.2004-1565
A more recent version of this article appeared on May 1, 2005
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*Compound via MeSH
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Hazardous Substances DB
*2,4-DINITROPHENOL
*GLUCOSE

Submitted on December 3, 2004
Accepted on January 18, 2005

AMPK and p38 MAPK Participate in the Stimulation of Glucose Uptake by Dinitrophenol in Adult Cardiomyocytes

Amélie Pelletier, Érik Joly, Marc Prentki, and Lise Coderre*

Montreal Diabetes Research Centre, Centre hospitalier de l'Université de Montréal (CHUM) and the Departments of Medicineand Nutrition, Université de Montréal, Montréal, Québec, Canada

* To whom correspondence should be addressed. E-mail: lise.coderre{at}umontreal.ca.

During metabolic stress, such as ischemia or hypoxia, glucose becomes the principal energy source for the heart. It has been shown that increased cardiac glucose uptake during metabolic stress has a protective effect on cell survival and heart function. Despite its physiological importance, only limited data are available on the molecular mechanisms regulating glucose uptake under these conditions. We used 2,4-dinitrophenol (DNP), an uncoupler of oxidative phosphorylation, as a model to mimic hypoxia and to gain insight into the signaling pathway underlying metabolic stress-induced glucose uptake in primary cultures of rat adult cardiomyocytes. The results demonstrate that 0.1 mM DNP induces 2.2- and 9-fold increases in AMPK and p38 MAPK phosphorylation, respectively. This is associated with a 2.3-fold increase in glucose uptake in these cells. To further delineate the role of AMPK in the regulation of glucose uptake, we used two complementary approaches: pharmacological inhibition of the enzyme with adenine 9-{beta}-D arabinofuranoside (AraA) and adenoviral infection with a dominant-negative AMPK (DN-AMPK) mutant. Our results show that overexpression of DN-AMPK completely suppressed DNP-mediated phosphorylation of acetyl CoA carboxylase, a downstream target of AMPK. Inhibition of AMPK with either AraA or DN-AMPK also abolished DNP-mediated p38 MAPK phosphorylation. Importantly, AMPK inhibition only partially decreased DNP-stimulated glucose uptake in cardiomyocytes. Inhibition of p38 MAPK with the pharmacological agent PD169316 also partially reduced (70%) glucose uptake in response to DNP. In conclusion, our results indicate that p38 MAPK acts downstream of AMPK in cardiomyocytes and that activation of the AMPK/p38 MAPK signaling cascade is essential for maximal stimulation of glucose uptake in response to DNP in adult cardiomyocytes.
Key words: Glucose Transport • Heart • AMPK • hypoxia • Metabolic Stress




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