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Gene Expression from the Imprinted Dio3 Locus Is Associated with Cell Proliferation of Cultured Brown Adipocytes

Departments of Medicine and Physiology (A.H.), Dartmouth Medical School, Lebanon, New Hampshire 03755; and Instituto de Investigaciones Biomédicas "Alberto Sols" (B.G., M.-J.O.), Consejo Superior de Investigaciones Cientificas and Universidad Autonoma de Madrid, 28029 Madrid, Spain

Address all correspondence and requests for reprints to: Arturo Hernandez, Ph.D., Research Assistant Professor of Medicine, Dartmouth Medical School, Borwell Building, Room 720W, Lebanon, New Hampshire 03755. E-mail: arturo.hernandez{at}dartmouth.edu.

Active thyroid hormones are critical for the differentiation and function of brown adipose tissue. However, we have observed high basal and induced levels of type 3 deiodinase (D3), an enzyme that inactivates thyroid hormones and is coded by the imprinted gene Dio3, in differentiating brown preadipocytes in primary culture. We find that D3 activity and mRNA expression strongly correlate with the rate of proliferation of undifferentiated precursor cells under various conditions. Furthermore, differentiation of precursor cells to adipocytes is associated with decreased levels of D3 expression, and only very low levels of D3 mRNA are found in mature adipocytes. Dlk1, an inhibitor of adipocyte differentiation and a paternally expressed gene located in the same imprinted domain as Dio3, displayed changes in expression that parallel those of Dio3. In contrast, a 4-kb transcript for Dio3os, an antisense gene also located in the same imprinted domain, is markedly up-regulated in differentiated adipocytes. We conclude that D3 expression in differentiating preadipocytes is primarily linked to proliferating cells, whereas Dio3os expression is associated with mature adipocytes. Our results suggest that genomic imprinting and gene expression at the Dlk1/Dio3 imprinted domain may play a role in the regulation of adipocyte proliferation and differentiation.

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