Mouse and human resistins impair glucose transport in primary mouse cardiomyocytes, and oligomerization is required for this biological action.
The adipocytokine resistin impairs glucose tolerance and insulin sensitivity in rodents. Here, we examined the effect of resistin on glucose uptake in isolated adult mouse cardiomyocytes. Murine resistin reduced insulin-stimulated glucose uptake, establishing the heart as a resistin target tissue. Notably, human resistin also impaired insulin action in mouse cardiomyocytes, providing the first evidence that human and mouse resistin homologs have similar functions. Resistin is a cysteine-rich molecule that circulates as a multimer of a dimeric form dependent upon a single intermolecular disulfide bond, which, in the mouse, involves Cys26; mutation of this residue to alanine (C26A) produces a monomeric molecule that appears to be bioactive in the liver. Remarkably, unlike native resistin, monomeric C26A resistin had no effect on basal or insulin-stimulated glucose uptake in mouse cardiomyocytes. Resistin impairs glucose uptake in cardiomyocytes by mechanisms that involve altered vesicle trafficking. Thus, in cardiomyocytes, both mouse and human resistins directly impair glucose transport; and in contrast to effects on the liver, these actions of resistin require oligomerization.
Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City, Utah 84112, USA.
Christophe
C
Graveleau
Vlad G
VG
Zaha
Arash
A
Mohajer
Ronadip R
RR
Banerjee
Nicole
N
Dudley-Rucker
Claire M
CM
Steppan
Michael W
MW
Rajala
Philipp E
PE
Scherer
Rexford S
RS
Ahima
Mitchell A
MA
Lazar
E Dale
ED
Abel
D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D019281:Dimerization; D005089:Exocytosis / Q000502:physiology; D005947:Glucose / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D006729:Hormones, Ectopic / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D052243:Resistin; D014168:Transferrin / Q000378:metabolism
D051275:Glucose Transporter Type 4; D006729:Hormones, Ectopic; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins; C499624:RETN protein, human; D052243:Resistin; C499623:Retn protein, mouse; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; D014168:Transferrin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose