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Brown adipose tissue (BAT) is a heater organ that expresses thermogenic uncoupling protein 1 (UCP1) to maintain high body temperatures during cold stress. BAT thermogenesis is considered an overarching mammalian trait, but its evolutionary origin is unknown. We show that adipose tissue of marsupials, which diverged from eutherian mammals ~ 150 million years ago, expresses a nonthermogenic UCP1 variant governed by a partial transcriptomic BAT signature similar to that found in eutherian beige adipose tissue. We found that the reconstructed UCP1 sequence of the common eutherian ancestor displayed typical thermogenic activity, whereas therian ancestor UCP1 is nonthermogenic. Thus, mammalian adipose tissue thermogenesis may have evolved in two distinct stages, with a prethermogenic stage in the common therian ancestor linking UCP1 expression to adipose tissue and thermal stress. We propose that in a second stage, UCP1 acquired its thermogenic function specifically in eutherians, such that the onset of mammalian BAT thermogenesis occurred only after the divergence from marsupials.

Promoting brown adipose tissue (BAT) activity innovatively targets obesity and metabolic disease. While thermogenic activation of BAT is well understood, the rheostatic regulation of BAT to avoid excessive energy dissipation remains ill-defined. Here, we demonstrate that adenylyl cyclase 3 (AC3) is key for BAT function. We identified a cold-inducible promoter that generates a 5' truncated AC3 mRNA isoform (Adcy3-at), whose expression is driven by a cold-induced, truncated isoform of PPARGC1A (PPARGC1A-AT). Male mice lacking Adcy3-at display increased energy expenditure and are resistant to obesity and ensuing metabolic imbalances. Mouse and human AC3-AT are retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and lack enzymatic activity. AC3-AT interacts with AC3 and sequesters it in the endoplasmic reticulum, reducing the pool of adenylyl cyclases available for G-protein-mediated cAMP synthesis. Thus, AC3-AT acts as a cold-induced rheostat in BAT, limiting adverse consequences of cAMP activity during chronic BAT activation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The molecular evolution of the mammalian heater protein UCP1 is a powerful biomarker to understand thermoregulatory strategies during species radiation into extreme climates, such as aquatic life with high thermal conductivity. While fully aquatic mammals lost UCP1, most semiaquatic seals display intact UCP1 genes, apart from large elephant seals. Here, we show that UCP1 thermogenic activity of the small-bodied harbor seal is equally potent compared to terrestrial orthologs, emphasizing its importance for neonatal survival on land. In contrast, elephant seal UCP1 does not display thermogenic activity, not even when translating a repaired or a recently highlighted truncated version. Thus, the thermogenic benefits for neonatal survival during terrestrial birth in semiaquatic pinnipeds maintained evolutionary selection pressure on UCP1 function and were only outweighed by extreme body sizes among elephant seals, fully eliminating UCP1-dependent thermogenesis., Competing Interests: Conflict of Interest We disclose no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Senescence-the deterioration of functionality with age-varies widely across taxa in pattern and rate. Insights into why and how this variation occurs are hindered by the predominance of laboratory-focused research on short-lived model species with determinate growth. We synthesize evolutionary theories of senescence, highlight key information gaps and clarify predictions for species with low mortality and variable degrees of indeterminate growth. Lake trout are an ideal species to evaluate predictions in the wild. We monitored individual males from two populations (1976-2017) longitudinally for changes in adult mortality (actuarial senescence) and body condition (proxy for energy balance). A cross-sectional approach (2017) compared young (ages 4-10 years) and old (18-37 years) adults for (i) phenotypic performance in body condition, and semen quality-which is related to fertility under sperm competition (reproductive senescence)-and (ii) relative telomere length (potential proxy for cellular senescence). Adult growth in these particular populations is constrained by a simplified foodweb, and our data support predictions of negligible senescence when maximum size is only slightly larger than maturation size. Negative senescence (aka reverse senescence) may occur in other lake trout populations where diet shifts allow maximum sizes to greatly exceed maturation size.

The thermogenic mechanisms supporting endothermy are still not fully understood in all major mammalian subgroups. In placental mammals, brown adipose tissue currently represents the most accepted source of adaptive non-shivering thermogenesis. Its mitochondrial protein UCP1 (uncoupling protein 1) catalyzes heat production, but the conservation of this mechanism is unclear in non-placental mammals and lost in some placentals. Here, we review the evidence for and against adaptive non-shivering thermogenesis in marsupials, which diverged from placentals about 120-160 million years ago. We critically discuss potential mechanisms that may be involved in the heat-generating process among marsupials., (© 2021. The Author(s).)

Brown adipose tissue (BAT), present in many placental mammals, provides adaptive nonshivering thermogenesis (NST) for body temperature regulation and has facilitated survival in diverse thermal niches on our planet. Intriguingly, several key details on the molecular mechanisms of NST and their potential ecophysiological adaptations are still unknown. Comparative studies at the whole animal level are unpragmatic, due to the diversity and complexity of thermoregulation among different species. We propose that the molecular evolution of mitochondrial uncoupling protein 1 (UCP1), a central component for BAT thermogenesis, represents a powerful opportunity to unravel key questions of mammalian thermoregulation. Comparative analysis of UCP1 may elucidate how its thermogenic function arose, how environmental selection has shaped protein function to support ecophysiological requirements, and how the enigmatic molecular mechanism of proton leak is governed. Several approaches for the assessment of UCP1 function in vitro have been introduced over the years. For comparative characterization of UCP1, we put forward the overexpression of UCP1 orthologues and mutated variants in a mammalian cell system as a primary strategy and discuss advantageous aspects in contrast to other experimental systems. In turn, we suggest how remaining experimental caveats can be solved by complimentary test systems before physiological consolidation in the animal model. Furthermore, we highlight the appropriate bioenergetic techniques to perform the functional analyses on UCP1. The comparative characterizations of diverse UCP1 variants may enable key insights into open questions surrounding the molecular basis of NST., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Uncoupling protein 1 (UCP1) governs non-shivering thermogenesis in brown adipose tissue. It has been estimated that pigs lost UCP1 ∼20 million years ago (MYA), dictating cold intolerance among piglets. Our current understanding of the root causes of UCP1 loss are, however, incomplete. Thus, examination of additional species can shed light on these fundamental evolutionary questions. Here, we investigated UCP1 in the Chacoan peccary ( Catagonus wagneri ), a member of the Tayassuid lineage that diverged from pigs during the late Eocene-mid Oligocene. Exons 1 and 2 have been deleted in peccary UCP1 and the remaining exons display additional inactivating mutations. A common nonsense mutation in exon 6 revealed that UCP1 was pseudogenized in a shared ancestor of pigs and peccaries. Our selection pressure analyses indicate that the inactivation occurred 36.2-44.3 MYA during the mid-late Eocene, which is much earlier than previously thought. Importantly, pseudogenized UCP1 provides the molecular rationale for cold sensitivity and current tropical biogeography of extant peccaries., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

In eutherian mammals, brown adipose tissue (BAT) permits non-shivering thermogenesis (NST) through high metabolic rates catalyzed by the unique mitochondrial uncoupling protein 1 (UCP1). The tissue has recently gained remarkable attention due to its discovery in adult humans. Approaching BAT and UCP1 as therapeutic targets to combust surplus energy bares high potential to combat the epidemic of the metabolic syndrome that has precipitated in our society as a result of our modern lifestyles. Our understanding of the physiological and molecular control of BAT may benefit tremendously from consideration of its evolution that basically outlines the blueprint of how to construct a fat burning tissue. Here, we discuss the evolutionary history of UCP1 and BAT, from its origins and emergence to its downfall in several mammalian lineages. Additionally, we delineate the annotation of UCPs in vertebrates by analyzing genomic organization and summarize the phylogeny of UCP1 within the closest relatives of humans, the great apes. Outlining whether the molecular networks controlling thermogenesis in adipose tissue (commonly known as the "browning potential") pre-dated the classical thermogenic function of BAT and UCP1, and whether the evolutionary inactivation of UCP1 enhanced compensatory thermogenic mechanisms, should be of major interest to those who aim to access adipose tissue thermogenesis in a biomedical context., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Uncoupling proteins (UCPs) belong to the mitochondrial anion carrier superfamily and catalyze important metabolic functions at the mitochondrial inner membrane. While the thermogenic role of UCP1 in brown fat of eutherian mammals is well established, the molecular functions of UCP1 in ectothermic vertebrates and of other UCP paralogs remain less clear. Here, we critically discuss the existence of brain UCPs and their potential roles. Applying phylogenetic classification of novel UCPs, we summarize the evidence for brain UCP1 among vertebrates, the role of UCP2 in specific brain areas, and the existence of brain-specific UCPs. The phylogenetic analyses and discussion on functional data should alert the scientific community that the molecular function of so-called UCP1 homologues is by far not clarified and possibly relates to neither thermogenesis nor mitochondrial uncoupling., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Brown adipose tissue (BAT), the specialized heat-producing organ found in many placental mammals including humans, may be accessible for clinical drug intervention to help combat metabolic diseases. Understanding the biology of BAT and its thermogenic uncoupling protein 1 (UCP1) will benefit from an assessment of its evolution, answering where UCP1 originated and how it has been modified and integrated into cellular energy metabolism. Here, we review topical insights regarding the molecular evolution of UCP1-also reconstructing the proximate and ultimate factors selecting for brown fat thermogenesis in placental mammals. This new thinking on "old" events will assist our understanding of how thermogenic mitochondrial uncoupling was integrated into the physiology of the brown adipocyte. Recent comparative studies examining the occurrence of UCP1 in vertebrates not only identified the ancient (pre-mammal) rise of UCP1 but also its repeated downfall during mammalian evolution as evidenced by multiple independent gene loss and/or inactivation events. Together with the comparative physiology of various species, we may be able to find conditions that favor UCP1 thermogenesis and, learning from these insights, identify molecular networks that will be useful to pharmacologically stimulate the tissue.

The high O 2 affinity of European mole (Talpa europaea) blood is postulated to largely arise from the presence of two β-globin chain residues (β4 Ser and β5 Gly) that weaken the interaction of its hemoglobin (Hb) with the red cell organophosphate 2,3-diphosphoglycerate (DPG). This latter trait is generally accepted to be an 'adaptation to subterranean life', despite the fact that no data are available for more basal mole lineages that have no evolutionary history of fossoriality (i.e. the ambulatory, high-elevation shrew-like moles and the semi-aquatic desmans), and which may similarly benefit from an elevated blood O 2 affinity. To test whether evolution of a low DPG sensitivity phenotype is linked to derived fossorial lifestyles or represents an ancestral trait for the family, we determined the globin gene sequences and measured the intrinsic O 2 affinity and co-factor sensitivity of the major Hb component of the gracile shrew-like mole (Uropsilus gracilis) and the Pyrenean desman (Galemys pyrenaicus). Our results unequivocally demonstrate that the presence of β4 Ser and β5 Gly, together with a low DPG sensitivity Hb phenotype, predates the radiation of the family Talpidae, and hence did not evolve as a specific adaptation to fossorial life. By contrast, our comparative analyses suggest that variations in whole blood O 2 affinity among members of this family predominantly arose from amino acid substitutions that increase or decrease the intrinsic O 2 affinity of the protein., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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.

Mitochondrial uncoupling protein 1 (UCP1) is essential for nonshivering thermogenesis in brown adipose tissue and is widely accepted to have played a key thermoregulatory role in small-bodied and neonatal placental mammals that enabled the exploitation of cold environments. We map ucp1 sequences from 133 mammals onto a species tree constructed from a ~51-kb sequence alignment and show that inactivating mutations have occurred in at least 8 of the 18 traditional placental orders, thereby challenging the physiological importance of UCP1 across Placentalia. Selection and timetree analyses further reveal that ucp1 inactivations temporally correspond with strong secondary reductions in metabolic intensity in xenarthrans and pangolins, or in six other lineages coincided with a ~30 million-year episode of global cooling in the Paleogene that promoted sharp increases in body mass and cladogenesis evident in the fossil record. Our findings also demonstrate that members of various lineages (for example, cetaceans, horses, woolly mammoths, Steller's sea cows) evolved extreme cold hardiness in the absence of UCP1-mediated thermogenesis. Finally, we identify ucp1 inactivation as a historical contingency that is linked to the current low species diversity of clades lacking functional UCP1, thus providing the first evidence for species selection related to the presence or absence of a single gene product.

The evolutionary fate of chimeric fusion genes may be strongly influenced by their recombinational mode of origin and the nature of functional divergence between the parental genes. In the β-globin gene family of placental mammals, the two postnatally expressed δ- and β-globin genes (HBD and HBB, respectively) have a propensity for recombinational exchange via gene conversion and unequal crossing-over. In the latter case, there are good reasons to expect differences in retention rates for the reciprocal HBB/HBD and HBD/HBB fusion genes due to thalassemia pathologies associated with the HBD/HBB "Lepore" deletion mutant in humans. Here, we report a comparative genomic analysis of the mammalian β-globin gene cluster, which revealed that chimeric HBB/HBD fusion genes originated independently in four separate lineages of laurasiatherian mammals: Eulipotyphlans (shrews, moles, and hedgehogs), carnivores, microchiropteran bats, and cetaceans. In cases where an independently derived "anti-Lepore" duplication mutant has become fixed, the parental HBD and/or HBB genes have typically been inactivated or deleted, so that the newly created HBB/HBD fusion gene is primarily responsible for synthesizing the β-type subunits of adult and fetal hemoglobin (Hb). Contrary to conventional wisdom that the HBD gene is a vestigial relict that is typically inactivated or expressed at negligible levels, we show that HBD-like genes often encode a substantial fraction (20-100%) of β-chain Hbs in laurasiatherian taxa. Our results indicate that the ascendancy or resuscitation of genes with HBD-like coding sequence requires the secondary acquisition of HBB-like promoter sequence via unequal crossing-over or interparalog gene conversion., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)