Abstract
The transcription factor C/EBPβ regulates hematopoiesis, bone, liver, fat, and skin homeostasis, and female reproduction. C/EBPβ protein expression from its single transcript occurs by alternative in-frame translation initiation at consecutive start sites to generate three isoforms, two long (LAP*, LAP) and one truncated (LIP), with the same C-terminal bZip dimerization domain. The long C/EBPβ isoforms are considered gene activators, whereas the LIP isoform reportedly acts as a dominant-negative repressor. Here, we tested the putative repressor functions of the C/EBPβ LIP isoform in mice by comparing monoallelic WT or LIP knockin mice with Cebpb knockout mice, in combination with monoallelic Cebpa mice. The C/EBPβ LIP isoform was sufficient to function in coordination with C/EBPα in murine development, adipose tissue and sebocyte differentiation, and female fertility. Thus, the C/EBPβ LIP isoform likely has more physiological functions than its currently known role as a dominant-negative inhibitor, which are more complex than anticipated.
Highlights
The transcription factor C/EBPβ regulates hematopoiesis, bone, liver, fat, and skin homeostasis, and female reproduction
The C/EBPβ LIP isoform was found in the WAT and BAT of −/L mice, and none of the isoforms were present in β−/− mice (Supplementary Fig. 2a BAT)
No significant decrease in the weight of gonadal fat pads was found in −/L mice (Fig. 1c), and adipocyte size was indistinguishable at 2–4 months and slightly increased at 12 months compared to β+/− controls (Fig. 1d,e)
Summary
The transcription factor C/EBPβ regulates hematopoiesis, bone, liver, fat, and skin homeostasis, and female reproduction. Considering the established view that C/EBPβ LIP is a genetic repressor, we recently observed that embryonic fibroblasts (MEF) generated from CebpbL/L knockin mice (L/L), expressing only the LIP isoform from its endogenous genetic locus, fail to differentiate into adipocytes in tissue culture (data not shown). These data corroborate the conclusions drawn from ectopic expression of C/EBPβ LIP in murine preadipocytic 3T3L1 cells[16], L/L animals developed white and brown fat. Statistical differences were assessed by two-way ANOVA within genotype (P < 0.0001) followed by Bonferroni post-hoc test with each time point. (c) Gonadal fat pad weight
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