Abstract
The resistin gene is expressed in adipocytes and encodes a protein proposed to link obesity and type 2 diabetes. Increased plasma FFA is associated with insulin resistance. We examined the effect of separate FFAs on the expression of resistin mRNA in cultured murine 3T3-L1 adipocytes. The FFAs tested did not increase resistin expression, whereas both arachidonic acid (AA) and eicosapentaenoic acid (EPA) reduced resistin mRNA levels. AA was by far the most potent FFA, reducing resistin mRNA levels to approximately 20% of control at 60-250 muM concentration. Selective inhibitors of cyclooxygenase-1 and of mitogen-activated protein kinase kinase counteracted AA-induced reduction in resistin mRNA levels. Transient overexpression of sterol-regulatory element binding protein-1a (SREBP-1a) activated the resistin promoter, but there was no reduction in the abundance of approximately 65 kDa mature SREBP-1 after AA exposure. Actinomycin D as well as cycloheximide abolished the AA-induced reduction of resistin mRNA levels, indicating dependence on de novo transcription and translation. Our data suggest that reductions in resistin mRNA levels involve a destabilization of the resistin mRNA molecule. An inhibitory effect of AA and EPA on resistin expression may explain the beneficial effect of ingesting PUFAs on insulin sensitivity.
Highlights
The resistin gene is expressed in adipocytes and encodes a protein proposed to link obesity and type 2 diabetes
To test whether fatty acids affect the transcriptional level of resistin expression, we differentiated 3T3-L1 adipocytes until day 8 or day 15 and incubated with vehicle (BSA) or with 250 M oleic acid (OA), linolenic acid (LN), arachidonic acid (AA), or eicosapentaenoic acid (EPA)
The level of resistin mRNA was significantly reduced at concentrations of у30 M in adipocytes incubated with AA, and expression levels at ف20% of the BSA control were observed at concentrations of 60–250 M (Fig. 1B)
Summary
The resistin gene is expressed in adipocytes and encodes a protein proposed to link obesity and type 2 diabetes. We examined the effect of separate FFAs on the expression of resistin mRNA in cultured murine 3T3-L1 adipocytes. The FFAs tested did not increase resistin expression, whereas both arachidonic acid (AA) and eicosapentaenoic acid (EPA) reduced resistin mRNA levels. AA was by far the most potent FFA, reducing resistin mRNA levels to ف20% of control at 60–250 M concentration. Resistin expression in 3T3-L1 adipocytes is reduced by arachidonic acid. Insulin inhibits hepatic glucose production when plasma glucose levels increase in mice, but resistin attenuates this effect of insulin, promoting increased plasma glucose concentration [16]. Transgenic expression of the mouse resistin gene in adipose tissue impaired oxidative and nonoxidative glucose disposal in skeletal muscle and promoted glucose intolerance [15]
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