Abstract
We have employed microarray technology using RNA from normal 3T3-L1 adipocytes and from 3T3-L1 adipocytes made insulin-resistant by treatment with tumor necrosis factor-alpha to identify a new class of insulin-responsive genes. These genes continued to respond normally to insulin even though the adipocytes themselves were metabolically insulin-resistant, i.e. they displayed a significantly decreased rate of insulin-stimulated glucose uptake. Approximately 12,000 genes/expressed sequence tags (ESTs) were screened. Of these, 40 genes/ESTs were identified that became insulin-resistant as expected (e.g. Socs-3, junB, and matrix metalloproteinase-11). However, 61 genes/ESTs continued to respond normally to insulin. Although some of these genes were previously shown to be regulated by insulin (e.g. Glut-1 and beta3-adrenergic receptor), other novel insulin-sensitive genes were also identified (e.g. Egr-1, epiregulin, Fra-1, and ABCA1). Real-time reverse transcription-PCR analysis confirmed the expression patterns of several of the differentially expressed genes. One gene that remained insulin-sensitive in the insulin-resistant adipocytes is the transcription factor Egr-1. Using an antisense strategy, we show that tissue factor and macrophage colony-stimulating factor, two cardiovascular risk factors, are downstream EGR-1 target genes in the adipocyte. Taken together, these data support the hypothesis that some signaling pathways remain insulin-sensitive in metabolically insulin-resistant adipocytes. These pathways may promote abnormal gene expression in hyperinsulinemic states like obesity and type II diabetes and thus may contribute to pathologies associated with these conditions.
Highlights
Determinants of fat mass [3,4,5,6]
This hypothesis is supported by previous observations showing that IR adipocytes and mice remained sensitive to insulin in terms of the expression of plasminogen activator inhibitor-1 (PAI-1) [12], sterol regulatory element-binding protein-1c [16], and monocyte chemoattractant protein-1 (MCP-1) [17]
By comparing the gene expression profiles of insulin-treated normal (N) 3T3-L1 adipocytes and metabolically IR 3T3-L1 adipocytes prepared by treatment with tumor necrosis factor-␣ (TNF-␣) [12], we have identified 61 genes/ expressed sequence tags (ESTs) that respond normally to insulin in IR adipocytes
Summary
Determinants of fat mass [3,4,5,6]. despite recent advancements in these fields, the molecular changes that contribute to these conditions and to the subsequent development of type II diabetes remain enigmatic. Resistance may promote the abnormal expression of these genes in insulin-responsive tissues This hypothesis is supported by previous observations showing that IR adipocytes and mice remained sensitive to insulin in terms of the expression of plasminogen activator inhibitor-1 (PAI-1) [12], sterol regulatory element-binding protein-1c [16], and monocyte chemoattractant protein-1 (MCP-1) [17]. Identification of the genes that continue to respond to insulin in IR adipocytes, in concert with studies of the properties of these genes and the signaling pathways that regulate them, may provide novel insights into the molecular mechanisms that control abnormal gene expression in obesity and type II diabetes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
