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Transcriptional Synergy and the Regulation of Ucp1 during Brown Adipocyte Induction in White Fat Depots

Bingzhong Xue, Ann Coulter, Jong Seop Rim, Robert A. Koza, and Leslie P. Kozak^*

Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, Louisiana

Received 25 March 2005/ Returned for modification 8 May 2005/ Accepted 18 June 2005

Induction of brown adipocytes in white fat depots by adrenergic stimulation is a complex genetic trait in mice that affects the ability of the animal to regulate body weight. An 80-fold difference in expression of the mitochondrial uncoupling gene (Ucp1) at the mRNA and protein levels between A/J and C57BL/6J (B6) mice is controlled by allelic interactions among nine quantitative trait loci (QTLs) on eight chromosomes. Overlapping patterns of these QTLs also regulate expression levels of Pgc-1, Ppar, and type 2 deiodinase. Independent validation that PPAR is associated with Ucp1 induction was obtained by treating mice with the PPAR agonist clofibrate, but not from the analysis of PPAR knockout mice. The most upstream sites of regulation for Ucp1 that differed between A/J and B6 were the phosphorylation of p38 mitogen-activated protein kinase and CREB and then followed by downstream changes in levels of mRNA for PPAR, PPAR, PGC-1, and type 2 deiodinase. However, compared to Ucp1 expression, the two- to fourfold differences in the expression of these regulatory components are very modest. It is proposed that small variations in the levels of several transcriptional components of the Ucp1 enhanceosome interact synergistically to achieve large differences in Ucp1 expression.

Present address: Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.

Present address: 202 Life Sciences Bldg., Louisiana State University, Baton Rouge, LA 70803.

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