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

Abstract

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.

Obesity and related consequences to ageing

“…Recent studies suggest that adult human BAT presents the molecular characteristics of rodent beige cells rather than classical BAT (Wu et al 2012). Animal studies showed relatively stable Ucp1 mRNA levels in adult mice (Xue et al 2005;Chabowska-Kita et al 2015); nonetheless, BAT activity was shown to diminish in ageing (Seale and Lazar 2009). It has been suggested that ageing may be associated with impaired thermogenesis as suggested by greater reduction of BAT activity in old men compared to young ones (Seale and Lazar 2009;McDonald and Horwitz 1999;Lin et al 2014).…”

PPARs and adipocyte function

“…Furthermore, they are prone to diet-induced obesity which paradoxically is associated with enhanced insulin sensitivity [92]. In contrast, clofibrate treatment was shown to lead to a "browning" of retroperitoneal WAT as evidenced by enhanced UCP1 expression [93]. In parallel, pharmacologic PPAR activation reduced adiposity in a variety of mouse models of dietinduced and genetic obesity.…”

“…Nonetheless, pharmacologic PPAR activation induces UCP1 gene expression in primary brown adipocytes and BAT in vivo [93,96]. Indeed, in transient transfection assays PPAR expression vectors stimulated activity of reporter genes driven by UCP1 promoter constructs.…”

Structure–effect relation of C18 long-chain fatty acids in the reduction of body weight in rats

“…26 Stimulation of b 3 -adrenergic receptors increases intracellular cAMP, thereby activating protein kinase A (PKA), which then phosphorylates the UCP1 transcription factor CREB and hormone-sensitive lipase, resulting in UCP1 Effect of C18 fatty acids on body weight O Vögler et al expression and lipolysis of stored fat from adipocyte lipid droplets. 27,28 Although one might speculate that these two physiological responses to b-adrenergic stimulation are independent of each other, a recent study has demonstrated that the b 3 -adrenergic agonist, CL-316,243, could reduce white-fat pad size and the size of adipocytes only in wildtype but not in UCP1 knockout mice. 29 A DNA microarray study of WAT from obese (fa/fa) Zucker rats treated with the b 3 -adrenoceptor agonist KTO-7924 revealed specifically enhanced mRNA expressions not only of UCP1 but also of COX8H, 30 which is the terminal enzyme of the mitochondrial respiratory chain 31 and likewise highly expressed in BAT.…”