Inactivation of thermogenic UCP1 as a historical contingency in multiple placental mammal clades

Gaudry, Michael J.; Jastroch, Martin; Treberg, Jason R.; Hofreiter, Michael; Paijmans, Johanna L. A.; Starrett, James; Wales, Nathan; Signore, Anthony V.; Springer, Mark S.; Campbell, Kevin L.

doi:10.1126/sciadv.1602878

Cited by 87 publications

(102 citation statements)

References 184 publications

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“…Consistent with the gain of function hypothesis, comparative phylogenetic analyses reveal that the stem eutherian branch is highly elongated in UCP1 gene trees relative to that of UCP2 and UCP3 paralogs (Saito et al, 2008 ; Hughes et al, 2009 ; Gaudry et al, 2017 ; Figure 1 ). It is thus likely that an elevated rate of non-synonymous UCP1 nucleotide substitutions in the stem eutherian branch conferred this protein with the ability to facilitate proton leak at physiologically significant levels (Jastroch et al, 2008 ; Klingenspor et al, 2008 ).…”

Section: Introductionmentioning

confidence: 59%

“…While the fat-tailed dunnart ( Sminthopsis crassicaudata ), a marsupial, displays a primitive “brownish” interscapular adipose depot that up-regulates UCP1 expression in response to cold exposure (Jastroch et al, 2008 ), this tissue is incapable of adaptive NST (Polymeropoulos et al, 2012 ) with no study demonstrating that UCP1 contributes to NST in marsupials. Although UCP1 appears to have been inactivated early in the evolution of the eutherian superorder Xenarthra (Gaudry et al, 2017 ), BAT-mediated adaptive thermogenesis is widely known to occur in small-bodied members of the superorders Laurasiatheria and Euarchontoglires (Oelkrug et al, 2015 ), and has been documented in the rock elephant shrew ( Elephantulus myurus ; Mzilikazi et al, 2007 ) and the lesser hedgehog tenrec ( Echinops telfairi ; Oelkrug et al, 2013 ), both members of the eutherian superorder Afrotheria. These observations strongly suggest that UCP1 was recruited for BAT-mediated NST in a common eutherian ancestor by gain of function mutations in the amino acid sequence of the protein and/or greater control over gene transcription that allowed highly concentrated UCP1 expression within BAT mitochondria (Klingenspor et al, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

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Evolution of UCP1 Transcriptional Regulatory Elements Across the Mammalian Phylogeny

Gaudry

Campbell

2017

Front. Physiol.

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Uncoupling protein 1 (UCP1) permits non-shivering thermogenesis (NST) when highly expressed in brown adipose tissue (BAT) mitochondria. Exclusive to placental mammals, BAT has commonly been regarded to be advantageous for thermoregulation in hibernators, small-bodied species, and the neonates of larger species. While numerous regulatory control motifs associated with UCP1 transcription have been proposed for murid rodents, it remains unclear whether these are conserved across the eutherian mammal phylogeny and hence essential for UCP1 expression. To address this shortcoming, we conducted a broad comparative survey of putative UCP1 transcriptional regulatory elements in 139 mammals (135 eutherians). We find no evidence for presence of a UCP1 enhancer in monotremes and marsupials, supporting the hypothesis that this control region evolved in a stem eutherian ancestor. We additionally reveal that several putative promoter elements (e.g., CRE-4, CCAAT) identified in murid rodents are not conserved among BAT-expressing eutherians, and together with the putative regulatory region (PRR) and CpG island do not appear to be crucial for UCP1 expression. The specificity and importance of the upTRE, dnTRE, URE1, CRE-2, RARE-2, NBRE, BRE-1, and BRE-2 enhancer elements first described from rats and mice are moreover uncertain as these motifs differ substantially—but generally remain highly conserved—in other BAT-expressing eutherians. Other UCP1 enhancer motifs (CRE-3, PPRE, and RARE-3) as well as the TATA box are also highly conserved in nearly all eutherian lineages with an intact UCP1. While these transcriptional regulatory motifs are generally also maintained in species where this gene is pseudogenized, the loss or degeneration of key basal promoter (e.g., TATA box) and enhancer elements in other UCP1-lacking lineages make it unlikely that the enhancer region is pleiotropic (i.e., co-regulates additional genes). Importantly, differential losses of (or mutations within) putative regulatory elements among the eutherian lineages with an intact UCP1 suggests that the transcriptional control of gene expression is not highly conserved in this mammalian clade.

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Section: Introductionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Evolution of UCP1 Transcriptional Regulatory Elements Across the Mammalian Phylogeny

Gaudry

Campbell

2017

Front. Physiol.

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“…However, to our knowledge, no studies have examined the two isoforms separately when measuring the transcriptional change of Ucp1 . Genetic mutations in Ucp1 to disrupt its thermogenic function occur in multiple mammalian species (Gaudry et al , ), so we wondered whether the two transcripts contribute equally to UCP1 production. The deposited mouse Ucp1 3′‐UTR sequence (NM_009463) contains two polyadenylation signals (AAUAAA), so we speculated that alternative polyadenylation may generate Ucp1 mRNA with short and long 3′‐UTRs, hereafter called Ucp1S and Ucp1L .…”

Section: Resultsmentioning

confidence: 99%

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

2018

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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.

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“…UCP1 gene was inactivated in numerous placental mammal clades (e.g. horses, whales, elephants, sea cows, hyraxes, sloths) and a number of these groups have species that are extremely cold tolerant, suggesting the existence of alternate NST mechanisms [111,112]. The whole swine family lost the UCP1 protein due to disruptions in the gene about 20 Ma [113].…”

Section: (B) Sarcolipin-based Thermogenesis In Mammals Lacking Brown mentioning

confidence: 99%

Uncoupling of sarcoendoplasmic reticulum calcium ATPase pump activity by sarcolipin as the basis for muscle non-shivering thermogenesis

Bal

Periasamy

2020

Phil. Trans. R. Soc. B

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Thermogenesis in endotherms relies on both shivering and non-shivering thermogenesis (NST). The role of brown adipose tissue (BAT) in NST is well recognized, but the role of muscle-based NST has been contested. However, recent studies have provided substantial evidence for the importance of muscle-based NST in mammals. This review focuses primarily on the role of sarcoplasmic reticulum (SR) Ca 2+ -cycling in muscle NST; specifically, it will discuss recent data showing how uncoupling of sarcoendoplasmic reticulum calcium ATPase (SERCA) (inhibition of Ca 2+ transport but not ATP hydrolysis) by sarcolipin (SLN) results in futile SERCA pump activity, increased ATP hydrolysis and heat production contributing to muscle NST. It will also critically examine how activation of muscle NST can be an important factor in regulating metabolic rate and whole-body energy homeostasis. In this regard, SLN has emerged as a powerful signalling molecule to promote mitochondrial biogenesis and oxidative metabolism in muscle. Furthermore, we will discuss the functional interplay between BAT and muscle, especially with respect to how reduced BAT function in mammals could be compensated by muscle-based NST. Based on the existing data, we argue that SLN-mediated thermogenesis is an integral part of muscle NST and that muscle NST potentially contributed to the evolution of endothermy within the vertebrate clade. This article is part of the theme issue ‘Vertebrate palaeophysiology’.

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Inactivation of thermogenic UCP1 as a historical contingency in multiple placental mammal clades

Abstract: Inactivation of uncoupling protein 1 is linked to shifts in metabolic rate, body size, and species richness of eight mammalian lineages.

Cited by 87 publications

References 184 publications

Evolution of UCP1 Transcriptional Regulatory Elements Across the Mammalian Phylogeny

Evolution of UCP1 Transcriptional Regulatory Elements Across the Mammalian Phylogeny

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

Uncoupling of sarcoendoplasmic reticulum calcium ATPase pump activity by sarcolipin as the basis for muscle non-shivering thermogenesis

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