Copyright © 2007, European Society of Cardiology
Globular and full-length forms of adiponectin mediate specific changes in glucose and fatty acid uptake and metabolism in cardiomyocytes
aDepartment of Biology, York University, Toronto, Ontario, Canada M3J 1P3
bGenome Research Center, University of Hong Kong, China
cDepartment of Medicine, University of Hong Kong, China
* Corresponding author. Tel: +1 416 736 2100x66635; fax: +1 416 736 5698. gsweeney{at}yorku.ca
Objective Our aim was to investigate the regulation of glucose and fatty acid metabolism in cardiomyocytes by the globular (gAd) and full-length (fAd) forms of adiponectin.
Methods We produced fAd (consisting of high, medium and low molecular weight oligomers) in a mammalian expression system and gAd in bacteria. These were used to treat primary neonatal rat cardiomyocytes (up to 48 h), and we employed 3H- or 14C-labeled substrates to monitor glucose uptake and subsequent metabolism via oxidation, glycogen synthesis or lactate production and fatty acid uptake and oxidation. Enzymatic assay for acetyl CoA carboxylase activity was employed, and protein phosphorylation and expression was determined by immunoblotting cell lysates. The role of adiponectin receptor (AdipoR) isoforms was determined via siRNA-mediated knockdown.
Results There was an initial (1 h) increase in glucose uptake and oxidation in response to gAd or fAd. Fatty acid uptake was stimulated by gAd or fAd, and by 24 h a decrease in acetyl CoA carboxylase activity and elevated fatty acid oxidation were observed. After 48 h increased fatty acid oxidation correlated with decreased glucose oxidation and pyruvate dehydrogenase activity, while glycogen synthesis and lactate production increased. Both gAd and fAd elicited phosphorylation of AMP kinase, insulin receptor substrate-1, Akt and glycogen synthase kinase-3β. Knockdown of AdipoR1 or AdipoR2 attenuated the effect of both gAd and fAd on fatty acid uptake and oxidation. Only AdipoR1 knockdown prevented the ability of gAd (1 h) to increase glucose uptake and oxidation; however, reducing either AdipoR1 or AdipoR2 expression attenuated the long-term (24 h) effects of gAd.
Conclusions These results clearly demonstrate that gAd and fAd mediate distinct and time-dependent effects on cardiomyocyte energy metabolism via AdipoR1 and AdipoR2.
KEYWORDS Adiponectin; Obesity; Diabetes; Glucose and fatty acid uptake and metabolism
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