CPEB 2‐dependent translation of long 3′‐ UTR Ucp1 mRNA promotes thermogenesis in brown adipose tissue

Abstract

Expression of mitochondrial proton transporter uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is essential for mammalian thermogenesis. While human UCP1 mRNA exists in a long form only, alternative polyadenylation creates two different isoforms in mice with 10% of UCP1 mRNA found in the long form (Ucp1L) and ~90% in the short form (Ucp1S). We generated a mouse model expressing only Ucp1S and found that it showed impaired thermogenesis due to a 60% drop in UCP1 protein levels, suggesting that Ucp1L is more efficiently translated than Ucp1S. In addition, we found that β3 adrenergic receptor signaling promoted the translation of mouse Ucp1L and human Ucp1 in a manner dependent on cytoplasmic polyadenylation element binding protein 2 (CPEB2). CPEB2-knockout mice showed reduced UCP1 levels and impaired thermogenesis in BAT, which was rescued by ectopic expression of CPEB2. Hence, long 3'-UTR Ucp1 mRNA translation activated by CPEB2 is likely conserved and important in humans to produce UCP1 for thermogenesis.

CPEB2-activated PDGFRα mRNA translation contributes to myofibroblast proliferation and pulmonary alveologenesis

“…We previously found that loss of CPEB2 in the dorsal motor nucleus of the vagus neurons leads to translational upregulation of choline acetyltransferase, thereby increasing pulmonary acetylcholine level to induce bronchoconstriction-associated apnea in neonatal pups [23]. However, surviving CPEB2-KO mice can live for at least 1 year without obvious physical problems except for reduced thermogenesis in brown adipose tissues [27]. To investigate whether the abnormal breathing patterns in neonatal CPEB2-KO mice persist into adulthood, we used a non-invasive whole-body plethysmography (WBP) to analyze their breathing patterns.…”

“…CPEB2 can bind to eukaryotic translation elongation factor 2 (eEF2) and downregulate eEF2's GTPase activity to impede translation of hypoxia-inducible factor 1α mRNA [24,25]. Similar to other CPEB family proteins, CPEB2 can also promote translation of some of its target mRNAs [26,27]. Previously, we found that CPEB2-KO neonatal mice showed aberrant respiration with frequent apnea and died mostly within 3 days after birth.…”

Alternative Polyadenylation and Differential Regulation of Ucp1: Implications for Brown Adipose Tissue Thermogenesis Across Species

“…The poly(A) site of Ucp1 in koala and gray short-tailed opossum in Marsupialia is located at 1,389 and 2,074 bp downstream of the stop codon, respectively, implying Ucp1 in both species may be subjected to more complex posttranscriptional regulation. Other than the 3′-UTRs of rat Ucp1S , mouse Ucp1S and Ucp1L , and human UCP1 having been confirmed by cDNA sequencing ( 17 , 18 , 21 ), the actual usage and preference of the two putative polyadenylation sites in other species require further investigation.…”

“…Northern blot analysis revealed two Ucp1 transcripts of ~1.5 and 1.9 kb (hereafter called Ucp1S and Ucp1L ) in mouse and rat BAT ( 15 , 16 ). The transcripts result from an alternative use of the poly(A) signal to yield 3′-UTRs of 78 and 485 bp in mice, respectively ( 21 ) ( Figure 1B ). By contrast, only the distal poly(A) signal is used to generate Ucp1L in rabbit BAT ( 20 ).…”

“…The human UCP1 coding sequence was identified by screening a genomic library with a rat Ucp1 cDNA probe, and a 1.9-kb UCP1 mRNA was detected in human perirenal BAT ( 22 ). More recently, the sequence of human UCP1 cDNA (ENST00000262999) revealed only one poly(A) site in the 3′-UTR, and RT-PCR analysis confirmed that human UCP1 encodes only the long form carrying a 465-bp 3′-UTR ( 21 ).…”