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The construction of morisco identity in the Spanish literary imaginary (1492-1614)
No full textThe expulsion of the moriscos from Spain between 1609 and 1614 marked the end of more than a century-long struggle for the New Christian population to be accepted within Christian Spanish society. From the moment they were forcibly baptised between 1499 and 1526 until they were ordered to leave the Peninsula, the moriscos faced constant and intense scrutiny from the church, crown, and their Old Christian neighbours regarding the sincerity of their faith. Through the expulsion orders that denounced them as heretics and apostates, the moriscos were treated as a single nation that was inherently Muslim, irrespective of their geographical origins, class, gender, or degree of assimilation within society. Over the course of the sixteenth century, the moriscos’ perceived intractable Otherness would be interpreted through two lenses: cultural and genealogical difference. Their preservation of cultural practices linked to their Muslim ancestors, as well as the refashioning of the limpieza de sangre statutes by official authorities, would cast the moriscos as an internal Other within Spain.
This study posits that the perception of the moriscos as an internal Other is a form of early modern race-making. Through the lenses of cultural and genealogical difference, what we see is the racialisation of religion, presenting the moriscos as irrevocably Muslim in spite of their conversion to Christianity. In the absence of phenotypic differences like skin colour, the moriscos’ racial Otherness was “identified” through other “visible,” or affected, differences, such as clothing and the speaking of Arabic, and the “invisible” difference of “impure” lineage. The study will reveal how the conceptualisation of the morisco figure in early modern Spanish literature centres around four rhetorics of race-making, which each serve to uncover or confirm the moriscos’ inherent Otherness through: their cultural differences; the changing relationship between the labels moro and morisco; the notion of limpieza de sangre; and the idea of the nación morisca. The study will explore the manifestation and perpetuation of these four rhetorics across a number of key literary discourses, including the novela morisca, romancero morisco, historical chronicles, drama, and prose fiction. It will also highlight how the image of the New Christian population in literary discourses revolves around three pivotal moments in the moriscos’ history: the fall of Granada, marking the end of Islamic rule within Spain (1492); the War of the Alpujarras (1568-1571), and the morisco expulsion (1609-1614).
Starting with the novela morisca genre in Chapter One, I will explore how the characterisation of the Granadan noble moros provides the foundations for the image of the moriscos as innately tied to their Muslim ancestry through their cultural practices. The importance of Arabic and morisco clothing in the collective imaginary is reinforced in the romancero morisco, a style of ballad whose resurgence can be attributed to the popularity of the novela morisca. The discord between the idealised world depicted in the novela morisca and the reality of the moriscos becomes apparent in Chapter Two, which details the events of the War of the Alpujarras. Looking at three major chronicles, I will explore how terminology became an important tool in defining the morisco as a religious Other, aligning the New Christian rebels with their ancestral faith through the renovation of the term moro. Chapter Three explores how the events of the civil war had serious repercussions on the collective image of the moriscos, with them all perceived as dangerous thereafter. In Lope de Vega’s dramatic verse, we see the potential threat that the moriscos posed to Spain emerge in plots that recognise the moriscos’ lack of fixed physical differences. Through the theme of passing, earlier rhetorics of race-making begin to be questioned, with Lope de Vega highlighting the performative nature of the moriscos’ cultural differences that are at the centre of Chapter One. Furthermore, within his drama, I will consider Lope de Vega’s focus on the third rhetoric of race-making, one which is based on the moriscos’ alleged genealogical difference: the concept of blood purity. Finally, Chapter Four will examine the representation of the nación morisca within Cervantes’s prose fiction. Written around the time of the expulsion, the collective image of the moriscos is one influenced by polemical writings that sought to characterise the moriscos as inherently incapable of following the Christian faith in order to justify the expulsion. And yet, Cervantes contradicts this essentialising image of the moriscos through individual characters who profess to be “true” Christians. With these characters, Cervantes challenges the notion that the moriscos were a homogenous group, instead revealing the heterogenous nature of the New Christian population. What is more, it is in Cervantes’s prose works that earlier rhetorics of race-making are once again challenged or dismantled.
By tracing the construction of morisco identity across various discourses throughout the sixteenth and early seventeenth centuries, this study reveals how these four rhetorics of race-making are embedded within the image of the morisco as a racialised, religious Other within Spain. And yet, while each author perpetuates the ideas of the church and crown that the moriscos were a distinct nation or race through these rhetorics, within each discourse we also see instances where these ideas are contested. The result is that, in engaging with these rhetorics of race-making to construct the morisco as a racialised, religious Other within Spain, these authors simultaneously assert and destabilise the essentialised image of the New Christian population, revealing the fallibility and artificiality of these rhetorics that sought to cast the moriscos as inherently different. Nevertheless, while these authors recognise that the moriscos were not all the same, nor were they inherently different from Old Christians, the potential danger they posed to Spain was a concern these authors could not shake. Consequently, the prevailing image of the moriscos is one shrouded in uncertainty. The authors’ repeated engagement with these essentialising rhetorics of race-making would subject the New Christians to perpetual suspicion, and would continue to influence the image of the moriscos within Spain’s collective imaginary long after their expulsion
Fragility, Institutions, and Fiscal Policy – A Critical Review
Full text linkThis policy brief examines fiscal governance in fragile and conflict-affected settings (FCAS) and its role in shaping institutions. Effective engagement requires moving beyond elite-focused analyses to consider broader societal and institutional impacts.
Fiscal governance interacts with security, justice, and service delivery institutions. Policies must account for historical governance structures, societal norms, and contemporary fiscal behaviors. Reform efforts should foster trust between citizens and the state by supporting inclusive state-society bargaining.
Realistic timelines for reform are essential, as rapid implementation risks creating policies that mimic stable states without achieving functionality. As aid budgets shrink, alternative investment sources, including private sector engagement, must be approached with sensitivity to institutional stability and conflict dynamics.
This brief calls for a holistic, politically aware approach to fiscal governance, urging international actors to bridge gaps between fiscal policy, governance, and peacebuilding. A deeper understanding of the institutional dimensions of fiscal practices is crucial for fostering long-term stability in FCAS
Climate impacts on species’ distributions in space and time
No full textAnthropogenic climate change is having major impacts on biodiversity, including driving shifts in species’ geographic distributions (occupancy and abundance). As a result, a major focus of contemporary eco-evolutionary research is on understanding how species’ distributions are changing, and predicting how they may continue to change in the future. To generate projections of species’ distributions under future climate scenarios, researchers often identify relationships between climate variables and species’ occupancy or abundance over geographic space and then project these spatial relationships over time. This ‘space-for-time substitution’ (SFTS) approach is very widely applied, but rests on key assumptions. In this thesis, I first conducted an extensive review of the use of the SFTS approach for predicting eco-evolutionary responses to climate change. I then used both empirical and simulated spatiotemporal abundance data to test the reliability of SFTS for projecting changes in species’ distributions under future climate change, as well as exploring the insights that can be gleaned from spatiotemporal abundance data.
After setting out the broad context of climate change and the potential utility of SFTS (Chapter 1), I then reviewed how SFTS are used in climate change ecology and evolution (Chapter 2), identifying how the approach is applied and its limitations. This review revealed that SFTS are widely used across different subfields (focusing on genotypes, phenotypes, species’ distributions and ecological communities) and that, while distinct disciplines appear to have progressed largely in isolation, they have arrived at broadly comparable methods. I also found that across all subfields, the SFTS approach relies on common but undertested assumptions relating to the identification of causal climate-distribution relationships in space and the transferability of these relationships over time (i.e. whether relationships are equivalent in space and time). Therefore, I arrived at the recommendations that there should be a focus on testing these key assumptions and that greater communication between different subfields would be of great benefit for the SFTS approach.
Having identified that there is a limited understanding of when spatial climate-distribution relationships can be reliably transferred over time, I then tested this using long-term UK-wide butterfly abundance data from the UK Butterfly Monitoring Scheme. First, in Chapter 3, I used the Orange-tip butterfly as a case study to develop an approach for comparing spatial and temporal climate-distribution relationships. Specifically, I first identified the seasonal periods over which temperature and precipitation variables best explained variation in Orange-tip abundance. Then, using these climate predictors, I decomposed climate variation into its spatial and temporal components, which allowed comparison of the spatial and temporal effects of temperature and precipitation variables on the Orange-tip’s occupancy and abundance across the species’ UK range. The aim of this work was to identify whether the temporal relationships between climate variables and each of abundance and occupancy were consistent with causality (i.e. non-zero and in the same direction) and equivalent to those observed over space, as is assumed when making SFTS projections. This revealed complex patterns in the level of equivalence between the spatial and temporal effects of temperature on the Orange-tip butterfly’s distribution, with variation both across the species’ range and between occupancy versus abundance. Conversely, precipitation appeared to not have a causal effect on the Orange-tip butterfly’s distribution, with little effect on occupancy or abundance over time. This emphasises the importance of identifying causal relationships before making projections; if the spatial precipitation-distribution relationships were assumed to be causal, they would generate misleading projections over time. Overall, this chapter demonstrates that the reliability of SFTS projections can be highly context-dependent, even for a single species, and this highlights the need for further exploration of when spatial relationships can be transferred over time.
In Chapter 4 I then extended this approach to consider seven univoltine butterfly species in the UK, with the aim of exploring the extent of variation in level of equivalence between spatial and temporal temperature-distribution relationships, both among and within species. Applying the methodology from Chapter 3 to multiple species revealed that both the causality of temperature-distribution relationships and the equivalence between relationships in space and time was highly variable across species, distribution metrics (occupancy versus abundance), and within a species’ climate range. The finding that temperature-distribution relationships for many species are unlikely to be causal – even when considering the seasonal periods of temperature that exhibited the strongest correlations with each species’ abundance – suggests that SFTS projections of species’ distributions under climate change may often be using non-causal relationships. In addition, even where relationships were consistent with causality, the slopes of the temporal temperature-distribution relationships were generally shallower than the local spatial slopes. This suggests that, over shorter timescales, species’ occupancies and abundances could not respond rapidly enough to track the temperature-distribution relationships observed over space and so SFTS projections may overestimate the magnitude of change in the near-term. Overall, these results add to Chapter 3 in emphasising the need to generate an understanding of the scenarios, including timescales, under which SFTS projections will be most reliable.
Finally, in Chapter 5, I aimed to address the dearth of theory relating to the application of SFTS that was revealed in my review of the field (Chapter 2). To achieve this, I used individual-based simulations, incorporating adaptation and gene flow in a stepping-stone model, to examine the patterns of spatial and temporal temperature-abundance relationships that are expected under a range of climate change, evolutionary and ecological scenarios. Spatial relationships between temperature and abundance were found to be humped in the presence of temperature-determined carrying capacities and humped with a plateaued peak when carrying capacities were constant across sites and years. In general, the slopes of the temporal temperature-abundance relationships were shallower than the local spatial slopes, with spatial and temporal slopes most similar under a weaker local adaptation scenario. This suggests that SFTS may often overestimate the magnitude of population responses to temperature changes over time and highlights the importance of considering the rates of processes operating in space and time. Additionally, where local adaptation was stronger, temperature-abundance relationships over time were found to be humped, suggesting that local adaptation leaves a discernible imprint on spatiotemporal abundance data and potentially offering an alternative to logistically challenging experimental approaches for detecting local adaptation. These results also suggest that local adaptation may undermine space-for-time projections of abundance changes in the short term, before populations have had time to adapt to new conditions. A key next step is to build on this work and test the utility of this approach in real world, multi-driver settings.
Taken together, my thesis demonstrates the risks of relying on SFTS for projecting species’ responses to climate change, and emphasises the need for further validation across different study systems and timescales. Specifically, I demonstrated how both the causality of climate-distribution relationships and the equivalence between spatial and temporal relationships can vary both across species and within an individual species’ range. Additionally, I found that temporal climate-distribution relationships were generally shallower than those seen in space, suggesting that responses in time may often lag behind climate change. This emphasises the importance of understanding the speed of processes operating over space and time, and how this affects the timescales over which SFTS projections are most reliable. Importantly, my empirical and simulation work also identified that spatiotemporal abundance data has been largely underutilised for testing the key assumptions of SFTS, with my simulations (Chapter 5) demonstrating that there may be unrealised potential for this type of data to detect local adaptation of populations to specific environmental drivers. Overall, my thesis demonstrated that considering spatial and temporal environmental effects together provides an opportunity to gain insights into the processes driving abundance trends and to improve the robustness of SFTS projections
Parallelizing graph computation with automated vectorization
No full textGraph computations have found widespread use in social network analysis, bioinformatics,
and web search. Applications often need to evaluate the same graph query multiple
times over the same data graph, starting from different source vertices, referred to as
multi-instance processing (MIP). There are mainly two approaches to MIP. The first
approach is to use highly optimized multi-instance graph algorithms that interleave the
evaluation of multiple query instances to exploit computation sharing across instances.
These multi-instance algorithms are efficient but challenging to implement. The other
approach is to use general-purpose graph processing frameworks and obtain answers to
multiple query instances through serial or batch evaluation. These frameworks are easy
to program but shown to be significantly less efficient than multi-instance algorithms.
With these two existing approaches, users have to choose between efficiency and ease of
programming. In response to the challenge, this thesis presents a systematic approach
to get the best of both worlds.
In the first part of this thesis, we present MITra, a framework for composing Multi-
Instance graph Traversal algorithms that traverse from multiple source vertices simultaneously
over a single thread. Underlying MITra is a frontier-ranking model, which
provides an abstraction for graph algorithms, separating traversal logic from computation
logic. Based on this model, MITra offers an easy-to-use programming interface.
MITra enables user to compose multi-instance algorithms by programming computation
logic in a dedicated edge function following textbook algorithms, and choosing
traversal logic via frontier-ranking configuration. On the backend, MITra synthesizes
and executes the multi-instance algorithm by automatically organizing vertices into
frontiers based on their numeric rank values, automatically sharing computation across
instances and benefiting from SIMD vectorization. We further showcase the ease of use,
expressiveness, and efficiency of MITra by developing a plug-and-play web demo. In
addition, we extend MITra to take advantage of multi-core parallelization, and evaluate
the performance of MITra through extensive experiments.
The second part of this thesis presents AutoMI, a framework for automatically converting
vertex-centric graph algorithms into their vectorized multi-instance versions. A
well-developed multi-instance algorithm runs significantly faster than traditional serial
and batch evaluation, however, its design and implementation are notoriously challenging.
AutoMI relieves the burden of writing delicate multi-instance algorithms from
developers and achieves superior performance through vectorization. In addition, we
propose TrackFree optimization in AutoMI, yielding simpler and more efficient multiiii
instance algorithm implementation. To aid the decision of whether to use TrackFree
in AutoMI, we develop an algebraic characterization. AutoMI targets vertex-centric
algorithms written in the GAS (Gather-Apply-Scatter) programming model, as promoted
by major distributed graph processing frameworks. We implement AutoMI and
demonstrate its performance advantage through extensive experiments on real-life and
synthetic data graphs.
Putting together, MITra and AutoMI provide a systematic approach to easily program
multi-instance graph algorithms and achieve high performance through automated
and effective vectorization
By the powers combined: the design and study of artificial metalloenzymes as photocatalysts
No full textPhotocatalysis is a powerful technique allowing the synthesis of products not easily accessible via traditional thermal chemistry. Transition metal complexes represent a major class of photocatalysts, with cyclometallated complexes of iridium(III) and ruthenium(II) being particularly prominent. However, the field of photocatalysis suffers from the difficulties experienced in controlling the enantioselectivity of the final product. In nature, enzymes catalyze reactions yielding products with extreme enantioselectivities. However, their scope is limited to reactions found in nature and can only utilize metals which are bio-available and natural co-factors (or their analogues) of the enzymes. This hampers the range of chemistry that can be achieved. Artificial metalloenzymes (ArM) aim to bridge the gap between the two catalysis regimes, by combining novel metals with proteins, to enable new-to-nature reactions with the advantage of increased enantioselectivity.
In the present work, two distinct methods were used to create novel photocatalytic ArMs and investigate their photophysical characteristics; introduction of an unnatural amino acid that capable of chelating Ir(III) into a naturally occurring protein and using coiled-coil peptide containing bipyridine sidechains which was designed de-novo to allow the binding of Ru(II).
The first strategy relied on the introduction of the unnatural amino acid bipyridine alanine (BpyAla) containing a 2,2’-bipyridine (bpy) side chain to the human Sterol Carrier Protein (SCP-2L). The bipyridine side chain can act as a binding site for the Ir(III) ion. Initially, 4 residues (V83, A100, Q111 and M112) on the protein scaffold were mutated to BpyAla and [Ir(ppy)2(bpy)]+ (where ppy = 2-phenylpyridine) bound on those sites. This library of 4 ArMs was studied to determine their photophysical properties, particularly the absorbance, fluorescence, quantum yields and excited state lifetimes, and limited structural study was carried out via circular dichroism spectroscopy. All the Ir-ArM variants showed a blue shifted fluorescence spectra compared to free [Ir(ppy)₂(bpy)]⁺. Further, all 4 ArMs showed an excited state lifetime more than twice as long as the free complex, and as high as 632 ns in the case of A100Bpy-Ir(ppy)₂ variant (vs 43 ns for the free complex). The incorporation of the Ir(III) center into the protein also resulted in up to 15x higher quantum yields vs free complex in aqueous solutions. Having formed and studied the photophysical properties of the Ir-ArM, a photocatalytic reaction was attempted (the homodimerization of chalcone) using the designed metalloenzyme as the catalyst. While the observed enantioselectivity was not very high with any of the modified proteins, the N-gly-M112Bpy-Ir(ppy)2 variant gave the highest e.e. (10%) of those tested. While attempts were made to introduce different Ir(III) complexes with various substituted phenylpyridine ligands to the protein, they proved unsuccessful.
Similar to enzymes found in nature, peptides can also be used to confer stereoselectivity in photocatalytic reactions. The second method of synthesising ArMs discussed in the following pages starts with de-novo designed peptides where the desired structural features can be incorporated at the design stage. Collaborators at the University of Bristol designed a hexameric coiled-coil peptide of the form A₃B₃ containing a hydrophobic tunnel, in which the peptide strand B contains BpyAla. Hydrophobic interactions pre-arrange the bipyridine residues in a manner which allows them to chelate Ru(II), to form an octahedral [Ru(bpy)₃]²⁺ complex, which is a well-known photocatalyst. The formation of the peptide-Ru ArM was followed by photophysical studies. When only peptide B was used to form [Ru(bpy)₃]²⁺ the excited state did not change appreciably form that observed for the free [Ru(bpy)₃]²⁺ complex in an aqueous solution. However, the coiled-coil system (PeptideA)₃(PeptideB)₃Ru(bpy)₃ showed a 7% longer lifetime vs [Ru(bpy)₃]²⁺. This system also showed drastically reduced quantum yield (0.6%) vs the free [Ru(bpy)₃]²⁺ complex (3.9%)
Weather shocks, conflict and effective, scalable interventions
Full text link‘Lightning talk’ presented by Nathan Jensen (University of Edinburgh) at the Jameel Observatory Community of Practice meeting, Addis Ababa, 13-14 May 202
Co-creation of a research agenda for localized anticipatory action in Somalia
No full textThis report was commissioned by Save the Children as a contribution to the ‘Reducing Impacts of Disasters Using the Anticipatory Action Framework in Somalia’ project funded by the Government of Germany. It sets out a set of research agendas that aim to address anticipatory action challenges prioritized in several in-country workshops
Improving access to geospatial climate risk data
Full text linkPlanning authorities in Scotland are required to prepare evidence reports as part of the local development plan (LDP) process. These provide a summary of the baseline data used and explain the implications of the LDP. Accurate, sub-national spatial data, which identifies geographic features such as rivers and utilities, is vital to create effective plans with a sound evidence base to evaluate climate risks. Fully evidencing climate risk requires an understanding of hazards, but also exposure and vulnerability, typically requiring interpretation of multiple datasets at once. This report explores the geospatial resources that are available to support the evidence gathering stage with a view to improving access to geospatial data on climate risk. It identifies existing data, data gaps, barriers, and resources needed for evidence-based planning and delivery
Using pangenomic approaches to analyse and refine meiotic recombination breakpoints in African trypanosomes
Full text linkTrypanosoma brucei is an African protozoan parasite which causes severe health and economic burden across sub-Saharan Africa, causing both Human and Animal African trypanosomiasis. Trypanosomes have previously been shown to undergo meiotic recombination in the salivary gland of the tsetse fly, which has the potential to influence genetic inheritance in hybrid progeny. Previously, MacLeod et al (2005), published a study that characterised hybrid progeny from genetic crosses between two parental strains of T. b. brucei – STIB 247 x TREU 927, following sexual recombination. They identified meiotic recombination events in the hybrid progeny, to the level of resolution possible with mini- and microsatellites. The work presented in this thesis builds upon the work of MacLeod et al., with the aim of understanding how meiotic recombination between two parental strains of T. b. brucei – TREU 927 Cl1 x STIB 247 Cl2 influences genotypic inheritance in twelve hybrid progeny, and aims to improve the resolution of the meiotic recombination events which were previously identified. This was achieved by generating multiple sequencing datasets for both the parental trypanosomes (Oxford Nanopore Technology [ONT] ultra-long reads, Pacific Bioscience [PacBio] HiFi reads, and Hi-C reads) and the progeny trypanosomes (ONT long reads, and Illumina whole genome sequencing (WGS) short reads), details of which are described in Chapter 2. Chapter 3 focuses on the genome assembly of both the parental and progeny genomes. As all downstream analysis was referenced against the parental trypanosomes – these assemblies had to be highly accurate, complete, contiguous assemblies. Both parental genomes were successfully assembled and haplotype-resolved, with contig N50s of 2.83 Mb and 3.57 Mb, consistent with most chromosomes being largely captured by individual contigs. In the final chapter, Chapter 4, a pangenome was generated comprising the genomes of the reference and parental genomes. This pangenome was used to map Illumina WGS reads from the progeny, to discern which parental haplotypes had been inherited by each of the progeny. 93 inferred recombination events were congruent with those identified in the previous microsatellite study, but mapped to a higher resolution, with a further 18 novel events identified. Furthermore, the frequency of meiotic recombination events was investigated, with the most events per Mb occurring on chromosome 4 (0.69 per Mb), and the fewest on chromosome 1 (0.09 per Mb). In total, all except for two meiotic recombination events were able to be refined, which substantially improved the resolution of the previous genetic map. This PhD project elucidates how genetic inheritance is affected by meiotic recombination in T. b. brucei, and the frequency at which sexual recombination occurs in hybrid progeny – e.g., which chromosomes experience chromosomal recombination ‘hotspots’ and ‘coldspots’. The outcomes of this PhD project could aid understanding of how meiotic recombination influences haplotypic content in hybrid progeny, and the implications this has in the field where both human-infective and non-human-infective trypanosomes circulate in the same geographic area. Additionally, further work could build upon this project to ascertain how the very large gene family (~2,000 genes) that is responsible for antigenic variation (the variant surface glycoprotein) segregates within the hybrid progeny, which could lead to a better understanding of how virulence genes are propagated in trypanosome populations through sexual recombination
Regulation of human brown adipose tissue activity
Full text linkThe rising prevalence of obesity globally poses significant morbidity and mortality, as obesity
increases the risk of developing a number of diseases such as diabetes, hypertension and
cardiovascular disease. While some more recent interventions to treat obesity have been
efficacious, they can cause undesirable side effects, highlighting a need for novel treatment
options. Adipose tissue comprises brown (BAT) and white adipose tissue (WAT). WAT mainly
stores energy, while BAT increases energy expenditure primarily through cold-induced
thermogenesis, which is mediated through a specialised thermogenic protein, called
uncoupling protein 1 (UCP1). Due to its role in thermogenesis, BAT has gained significant
interest as a target to treat obesity and associated cardiometabolic disease. 2-deoxy-2-
[¹⁸F]fluoro-D-glucose (¹⁸F-FDG) positron emission tomography (PET) is the most commonly
used technique to quantify human BAT mass and activity, exploiting the substantial glucose
uptake by BAT as a surrogate marker for BAT thermogenesis. The prevalence of detectable
BAT at room temperature using ¹⁸F-FDG PET is reduced in individuals with increased
cardiovascular risk such as obesity, diabetes and hypertension. However, ¹⁸F-FDG uptake by
BAT may be confounded by obesity-induced insulin resistance so it remains unclear whether
BAT thermogenesis is decreased in obesity and cardiometabolic disease. Our understanding
of the regulation of human BAT activation also remains limited. Using transcriptomics, we
recently identified serotonin as a potential regulator of human BAT, by demonstrating that
the gene SLC6A4, which encodes the serotonin reuptake transporter (SERT), was one of the
most differentially expressed genes in human brown compared with white adipocytes. SERT
inhibition, which increases serotonin receptor activation, decreased human brown adipocyte
thermogenesis. However, it is unknown whether serotonin levels are altered in obesity or if
reduction in peripheral serotonin activity can lead to a therapeutic benefit.
We hypothesised that (1) UCP1 expression in human BAT, a marker of BAT thermogenic
capacity, is inversely associated with cardiovascular risk factors, (2) circulating and adipose
tissue serotonin levels are increased in obesity and (3) inhibition of peripheral serotonin
synthesis stimulates human BAT activity.
To assess hypothesis 1, we measured UCP1 mRNA expression in whole adipose tissue (n=53)
and in differentiated pre-adipocytes (n=85) from paired BAT and WAT biopsy samples
obtained from patients undergoing elective neck surgery. UCP1 expression in BAT (but not in
WAT or in differentiated brown or white pre-adipocytes) was inversely associated with
obesity, ageing, insulin resistance and hypertension. Age was the only independent predictor
of high UCP1 expression in BAT and obesity reduced the frequency of high UCP1 expression
only in individuals >40 years. To explore the effect of obesity in young adults in vivo, ¹⁸F-FDG
PET-MR scans were performed in young obese and age-matched normal weight individuals
(n=6 in each weight group, mean age ~22 years) following 2 hours of mild cold exposure.
Consistent with the UCP1 data, young individuals with obesity had preserved ¹⁸F-FDG uptake
by BAT, despite increased insulin resistance.
To determine if obesity alters peripheral serotonin levels, we measured circulating and
abdominal adipose tissue serotonin concentrations in healthy age-matched individuals with
normal body weight and obesity (n=10 in each weight group) during warm and cold exposure.
The majority of circulating serotonin is inactive due to being platelet-bound with only a small
proportion circulating freely. Platelet serotonin concentrations increased during cold
exposure in normal weight individuals. However, in obese volunteers, inactive platelet
serotonin levels increased during warm conditions, which dropped during cold exposure,
accompanied by an increase in adipose tissue serotonin levels. These variations in serotonin
concentrations suggest a potential dysregulation in cold-induced serotonin response in
obesity.
To assess whether inhibition of peripheral serotonin synthesis altered BAT activity, we
undertook a double-blind crossover study in 8 healthy normal weight subjects and 8
participants with obesity. These volunteers were given placebo and telotristat ethyl tablets
(an inhibitor of peripheral serotonin synthesis) for 2 weeks in random order. Telotristat ethyl
reduced ¹⁸F-FDG uptake by BAT, increased total cholesterol levels and suppressed the rise in
noradrenaline and insulin levels following cold exposure and oral glucose load respectively.
In conclusion, UCP1 expression in BAT is reduced with ageing, obesity and cardiometabolic
disease, in keeping with BAT dysfunctio
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