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MicroRNA 132 Regulates Nutritional Stress-Induced Chemokine Production through Repression of SirT1

Departments of Metabolic Discovery Technology Group (J.C.S., J.H.J., H.X., A.H., A.A., K.M.W.), Computational Biology (J.W.), and Gene Cloning (J.F.), GlaxoSmithKline, Inc., Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Jay C. Strum, 450 West Drive, Rm 21-232, Chapel Hill, North Carolina 27599-7295. E-mail: jaystrum{at}msn.com.

Human adipose tissue secretes a number of proinflammatory mediators that may contribute to the pathophysiology of obesity-related disorders. Understanding the regulatory pathways that control their production is paramount to developing effective therapeutics to treat these diseases. Using primary human adipose-derived stem cells as a source of preadipocytes and in vitro differentiated adipocytes, we found IL-8 and monocyte chemoattractant protein-1 (MCP-1) are constitutively secreted by both cell types and induced in response to serum deprivation. MicroRNA profiling revealed the rapid induction of microRNA 132 (miR-132) in these cells when switched to serum-free medium. Furthermore, miR-132 overexpression was sufficient to induce nuclear factor-B translocation, acetylation of p65, and production of IL-8 and MCP-1. Inhibitors of miR-132 decreased acetylated p65 and partially inhibited the production of IL-8 and MCP-1 induced by serum deprivation. MiR-132 was shown to inhibit silent information regulator 1 (SirT1) expression through a miR-132 binding site in the 3'-untranslated region of SirT1. Thus, in response to nutritional availability, induction of miR-132 decreases SirT1-mediated deacetylation of p65 leading to activation of nuclear factor-B and transcription of IL-8 and MCP-1 in primary human preadipocytes and in vitro differentiated adipocytes.