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Necdin and E2F4 Are Modulated by Rosiglitazone Therapy in Diabetic Human Adipose and Muscle Tissue

¹ Research Division, Joslin Diabetes Center, Boston, Massachusetts
² Harvard Medical School, Boston, Massachusetts
³ Division of Regulation of Macromolecular Function, Institute for Protein Research, Osaka University, Osaka, Japan
⁴ Digital Gene Technologies/Neurome, La Jolla, California

Address correspondence and reprint requests to Allison B. Goldfine, MD, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: allison.goldfine{at}joslin.harvard.edu

Abbreviations: CEBP-, CAAAT/enhancer-binding protein-; PPAR-, peroxisome proliferator–activated receptor-; Pref-1, preadipocyte factor 1; TOGA, Total Gene Expression Analysis; TZD, thiazolidinedione

To identify novel pathways mediating molecular mechanisms of thiazolidinediones (TZDs) in humans, we assessed gene expression in adipose and muscle tissue from six subjects with type 2 diabetes before and after 8 weeks of treatment with rosiglitazone. mRNA was analyzed using Total Gene Expression Analysis (TOGA), an automated restriction-based cDNA display method with quantitative analysis of PCR products. The expression of cell cycle regulatory transcription factors E2F4 and the MAGE protein necdin were similarly altered in all subjects after rosiglitazone treatment. E2F4 expression was decreased by 10-fold in muscle and 2.5-fold in adipose tissue; necdin was identified in adipose tissue only and increased 1.8-fold after TZD treatment. To determine whether changes were related to an effect of the drug or adipogenesis, we evaluated the impact of rosiglitazone and differentiation independently in 3T3-L1 adipocytes. While treatment of differentiated adipocytes with rosiglitazone did not alter E2F4 or necdin, expression of both genes was significantly altered during differentiation. Differentiation was associated with increased cytosolic localization of E2F4. Moreover, necdin overexpression potently inhibited adipocyte differentiation and cell cycle progression. These data suggest that changes in necdin and E2F4 expression after rosiglitazone exposure in humans are associated with altered adipocyte differentiation and may contribute to improved insulin sensitivity in humans treated with TZDs.

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