The adipokine resistin has been proposed to link obesity, insulin resistance and 
diabetes. We have previously reported that diabetic hearts express high levels 
of resistin while overexpression of resistin in adult rat hearts gives rise to a 
phenotype resembling diabetic cardiomyopathy. The transcriptional regulation of 
resistin in diabetic cardiac tissue is currently unknown. This study 
investigated the mechanism of resistin upregulation and the role of Serca2a in 
its transcriptional suppression. We demonstrate that restoration of Ca2+ 
homeostasis in diabetic hearts, through normalization of Serca2a function 
genetically and pharmacologically, suppressed resistin expression via inhibition 
of NFATc. H9c2 myocytes stimulated with high-glucose concentration or Ca2+ 
time-dependently increased NFATc and resistin expression while addition of the 
Ca2+ chelator BAPTA-AM attenuated this effect. NFATc expression was enhanced in 
hearts from ob/ob diabetic and from cardiac-specific Serca2a-/- mice. Similarly, 
NFATc increased resistin expression in myocytes cultured in low glucose while 
the NFATc inhibitor VIVIT blocked glucose-induced resistin expression, 
suggesting that hyperglycemia/diabetes induces resistin expression possibly 
through NFATc activation. Interestingly, overexpression of Serca2a or VIVIT 
mitigated glucose-stimulated resistin and NFATc expression and enhanced AMPK 
activity, a downstream target of resistin signaling. NFATc direct activation of 
resistin was verified by resistin promoter luciferase activity and 
chromatin-immunoprecipitation analysis. Interestingly, activation of Serca2a by 
a novel agonist, CDN1163, mirrored the effects of AAV9-Serca2a gene transfer on 
resistin expression and its promoter activity and AMPK signaling in diabetic 
mice. These findings parse a role for Ca2+ in resistin transactivation and 
provide support that manipulation of Serca2a-NFATc-Resistin axis might be useful 
in hyper-resistinemic conditions.