Pref-1 in brown adipose tissue: specific involvement in brown adipocyte differentiation and regulatory role of C/EBPδ

Abstract

Pref-1 (pre-adipocyte factor-1) is known to play a central role in regulating white adipocyte differentiation, but the role of Pref-1 in BAT (brown adipose tissue) has not been analysed. In the present study we found that Pref-1 expression is high in fetal BAT and declines progressively after birth. However, Pref-1-null mice showed unaltered fetal development of BAT, but exhibited signs of over-activation of BAT thermogenesis in the post-natal period. In C/EBP (CCAAT/enhancer-binding protein) α-null mice, a rodent model of impaired fetal BAT differentiation, Pref-1 was dramatically overexpressed, in association with reduced expression of the Ucp1 (uncoupling protein 1) gene, a BAT-specific marker of thermogenic differentiation. In brown adipocyte cell culture models, Pref-1 was mostly expressed in pre-adipocytes and declined with brown adipocyte differentiation. The transcription factor C/EBPδ activated the Pref-1 gene transcription in brown adipocytes, through binding to the proximal promoter region. Accordingly, siRNA (small interfering RNA)-induced C/EBPδ knockdown led to reduced Pref-1 gene expression. This effect is consistent with the observed overexpression of C/EBPδ in C/EBPα-null BAT and high expression of C/EBPδ in brown pre-adipocytes. Dexamethasone treatment of brown pre-adipocytes suppressed Pref-1 down-regulation occurring throughout the brown adipocyte differentiation process, increased the expression of C/EBPδ and strongly impaired expression of the thermogenic markers UCP1 and PGC-1α [PPARγ (peroxisome-proliferator-activated receptor γ) co-activator-α]. However, it did not alter normal fat accumulation or expression of non-BAT-specific genes. Collectively, these results specifically implicate Pref-1 in controlling the thermogenic gene expression program in BAT, and identify C/EBPδ as a novel transcriptional regulator of Pref-1 gene expression that may be related to the specific role of glucocorticoids in BAT differentiation.

Berardinelli-Seip Congenital Lipodystrophy 2/Seipin Is Not Required for Brown Adipogenesis but Regulates Brown Adipose Tissue Development and Function

“…1D, left panel). In line with a previous report (35), the expression of Ucp1 mRNA was initiated in late fetal life (E18.5) and followed the same kinetic pattern as Bscl2 postnatally (Fig. 1D, right panel).…”

“…Mice were maintained under standard conditions with controlled 12-h/12-h light-dark cycle and 21 Ϯ 1°C room temperature. For studies in fetuses and neonates, interscapular BAT was carefully dissected under microscopy as previously described (35). Samples from two or three pups were pooled for each experimental condition for mRNA and protein analyses.…”

Cold Exposure Partially Corrects Disturbances in Lipid Metabolism in a Male Mouse Model of Glucocorticoid Excess

“…A number of in vivo and in vitro studies show that GCs inhibit BAT activity, most likely via a GC receptor-mediated pathway (42)(43)(44)(45)(46). In addition, adrenalectomy of rodents resulted in increased BAT activity, which was normalized by GC replacement (47,48).…”

Pref-1, a Gatekeeper of Adipogenesis

“…As in WAT, however, it is known that Pref-1 is downregulated during BAT development, being present at a very high level in fetuses but decreasing to an undetectable level several weeks after birth (32). Though BAT appeared to be normal prior to birth, Pref-1 ablated mice show altered BAT morphology after birth, with potential thermogenic over-activation, indicated by the induction of thermogenic markers and enhanced lipid mobilization.…”

“…An indirect mechanism of this effect may be through the DEX-mediated induction of C/EPBδ, as was recently demonstrated by Armengol et al . (32). Taken together, these results demonstrate that Pref-1 plays an important role in the regulation of both WAT and BAT differentiation.…”