Necdin and E2F4 Are Modulated by Rosiglitazone Therapy in Diabetic Human Adipose and Muscle Tissue
- Allison B. Goldfine12,
- Sarah Crunkhorn1,
- Maura Costello1,
- Hiral Gami1,
- Edwin J. Landaker1,
- Michio Niinobe3,
- Kazuaki Yoshikawa3,
- David Lo4,
- Amy Warren4,
- Jose Jimenez-Chillaron1 and
- Mary Elizabeth Patti12
- 1Research Division, Joslin Diabetes Center, Boston, Massachusetts
- 2Harvard Medical School, Boston, Massachusetts
- 3Division of Regulation of Macromolecular Function, Institute for Protein Research, Osaka University, Osaka, Japan
- 4Digital 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
Abstract
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.
- CEBP-α, CAAAT/enhancer-binding protein-α
- PPAR-γ, peroxisome proliferator–activated receptor-γ
- Pref-1, preadipocyte factor 1
- TOGA, Total Gene Expression Analysis
- TZD, thiazolidinedione
Footnotes
-
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
A.B.G. and S.C. contributed equally to this work.
D.L. is currently affiliated with the La Jolla Institute for Allergy and Immunology, San Diego, California.
Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.
-
- Accepted November 18, 2005.
- Received August 8, 2005.
- DIABETES
