Transcriptional synergy and the regulation of Ucp1 during brown adipocyte induction in white fat depots

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 (136) 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 alpha, Ppar alpha, and type 2 deiodinase. Independent validation that PPAR alpha is associated with Ucp1 induction was obtained by treating mice with the PPAR alpha agonist clofibrate, but not from the analysis of PPAR alpha knockout mice. The most upstream sites of regulation for Ucpl that differed between A/J and 136 were the phosphorylation of p38 mitogen-activated protein kinase and CREB and then followed by downstream changes in levels of mRNA for PPAR gamma, PPAR alpha, PGC-1 alpha, and type 2 deiodinase. However, compared to Ucpl 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 Ucpl expression.