Mouse and Human Resistins Impair Glucose Transport in Primary Mouse Cardiomyocytes, and Oligomerization Is Required for This Biological Action

Abstract

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 insulinstimulated 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 cysteinerich molecule that circulates as a multimer of a dimeric form dependent upon a single intermolecular disulfide bond, which, in the mouse, involves Cys 26 ; 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.

Neutrophil-Derived Hyperresistinemia in Severe Acute Streptococcal Infections

“…Furthermore, two recent reports described immunosuppressive effects of resistin on immune cells, including interference with chemotactic and oxidative responses of neutrophils (29), as well as suppression of Ag uptake and presentation by dendritic cells (30). Yet another level of complexity is added by the fact that resistin has a tendency to form oligomers both in vitro and in vivo (31)(32)(33). This oligomerization has been suggested to affect resistin's biological functions and hence will be an important factor to consider in future studies.…”

The role of resistin as a regulator of inflammation: Implications for various human pathologies

“…Moreover, resistin has been shown to impair glucose metabolism in mouse cardiomyocytes and to worsen cardiac ischemia-reperfusion injury in rats. This could be due to stimulated cardiac TNF-α secretion and the reperfusion release of 13 natriuretic peptides and biochemical markers of myocardial damage [14,87]. Furthermore, the abnormal formation of blood vessels also plays a role in other pathologies such as tumors, diabetic retinopathy, rheumatoid arthritis, or systemic lupus erythematosus.…”

“…In contrast to the liver, the biological action of resistin in the cardiac muscle of mice requires oligomerization [14].…”

Sitagliptin decreases ventricular arrhythmias by attenuated glucose-dependent insulinotropic polypeptide (GIP)-dependent resistin signalling in infarcted rats

“…In addition, although resistin mRNA expression levels have been reported to be the highest in white adipose tissue in rodents, resistin has also been found to be expressed in the heart [8]. Resistin has also been shown to impair glucose transport in isolated cardiomyocytes [9] and to be upregulated by cyclic stretch and aorta-caval shunt [10], suggesting that resistin mRNA is expressed in cardiomyocytes.…”