Anopheles stephensi is a potent vector of malaria throughout the Indian subcontinent and Middle East. An. stephensi is emerging as a model for molecular and genetic studies of mosquito-parasite interactions. Here we conducted a series of genomic and transcriptomic studies to improve the understanding of the biology of Anopheles stephensi and mosquito in general. First we reported the genome sequence and annotation of the Indian strain of the type form of An. stephensi. The 221 Mb genome assembly was produced using a combination of 454, Illumina, and PacBio sequencing. This hybrid assembly method was significantly better than assemblies generated from a single data source. A total of 11,789 protein-encoding genes were annotated using a combination of homology and de novo prediction. Secondly, we demonstrated the presence of complete dosage compensation in An. stephensi by determining that autosomal and X-linked genes have very similar levels of expression in both males and females. The uniformity of average expression levels of autosomal and X-linked genes remained when An. stephensi gene expression was normalized by that of their Ae. aegypti orthologs, strengthening the conclusion of complete dosage compensation in Anopheles. Lastly, we investigated trans-splicing events in Anopheles stephensi. We identified six trans-splicing events and all the trans-splicing sites are conserved and present in Ae. aegypti. The proteins encoded by the trans-spliced mRNAs are also highly conserved and their orthologs are co-linearly transcribed in out-groups of family Culicidae. This finding indicates the need to preserve the intact mRNA and protein function of the broken-up genes by trans-splicing during evolution. In summary, we presented the first genome assembly of Anopheles stephensi and studied two interesting evolution events" dosage compensation and trans-splicing - via transcriptomic analysis. / Ph. D.

Across the animal kingdom, predation is a ubiquitous and omnipresent selective agent for a variety of traits. I aimed to address gaps in our knowledge pertaining to how predation shapes animal behavior. Many species of fish naturally occur in drainages that differ in the density of predators and exhibit obvious population divergence, making them ideal study organisms to investigate predator-driven behavioral evolution. In Chapter 1, I conducted a systematic review of the literature. The purpose of this review was to determine if predation acted as a stronger or weaker selective agent on particular behavioral traits (e.g., foraging, mating, antipredator etc.) across fish. This review showed that predation does not always drive behavior in predictable ways, and that some behavioral traits more consistently diverge than others. It was evident that antipredator behaviors are extremely variable but were typically measured in response to a visual stimulus. Investigations on intraspecific variation pertaining to how fish acquire, process, and respond to information across other sensory modalities are needed. To address this, I focused on a Neotropical fish, Brachyrhaphis rhabdophora (Poeciliidae), from Costa Rica that occur in distinct predation environments. For Chapter 2, I evaluated whether males and females exhibit differential responses to conspecific chemical alarm cues. Chemical alarm cues are released when a prey is injured by a predator and are an honest indicator of risk. It was clear that B. rhabdophora responded to alarm cues, but that males and females sometimes employed different antipredator strategies depending on what predation environment they were from. However, we know that in group-living species, such as B. rhabdophora, risk information can also be acquired indirectly through social cues. There are tradeoffs associated with relying on direct vs. indirect information, and these sources of information may sometimes conflict. For Chapter 3 I considered how B. rhabdophora integrates conflicting information to elicit antipredator behavior. I again exposed fish directly to chemical alarm cues and measured how their antipredator responses changed when visually observing conflicting or reinforcing social information. I found that individuals integrated personal and social information differently based on their evolutionary history with predators. Further, we found evidence that even a single observer fish is able to influence group behavior. Finally, for Chapter 4, I evaluated sex-specific variation in brain size across predation environments. According to the "expensive-tissue hypothesis" there should only be investment in brain tissue when there is sufficient selection for enhanced cognitive abilities. Prey under elevated selection from predators should invest more in cognitive traits to enhance survival, but how sex interplays with this effect is unclear. I found that females had higher relative total brain volumes than males, but males exhibited more variation across predation environments in the relative volumes for certain brain regions. This work as a whole suggests that, yes, evolutionary history matters for a variety of sensory-related traits in B. rhabdophora.

Background: Obesity-associated metabolic complications display sexual dimorphism and can be impacted by cytokines. We previously showed that interleukin-10 (IL-10) was upregulated in white adipose tissue (WAT) of obese women with type 2 diabetes (T2D). Whether this pertains to men is unknown. The aim of this study was to compare the impact of obesity and T2D on WAT IL- 10 levels in men versus women. Methods: Plasma and subcutaneous WAT biopsies were obtained from 108 metabolically well-characterized individuals. WAT IL10 expression/secretion and WAT-resident IL-10-secreting macrophage number were measured. Circulating sex hormone levels were correlated toWAT IL10 expression in 22 individuals and sex hormone effects on macrophage IL10 expression were investigated in vitro. Results: Obese women with T2D showed increased IL10 expression/secretion and IL-10-secreting WAT macrophage number compared to other female groups. This difference was absent in men. Non-obese women and men with T2D showed similar IL-10 levels compared to healthy controls, indicating that T2D alone does not regulate IL-10. Although WAT IL10 expression correlated with serum estrone (E1) concentrations, recombinant E1 did not affect macrophage IL10 expression in vitro. Conclusion: WAT IL-10 levels are higher in women with obesity and T2D, but not in men and this effect is primarily attributed to obesity per se. This is less likely to be driven by circulating sex hormones. We propose that the WAT IL-10 might exert protective effects in obesity-associated chronic inflammation in women which could be one of the contributing factors for the decreased morbidity observed in women during obesity than men.

No description available.

Se ist ein essentielles Spurenelement, das seine biologische Aktivität als Selenocystein in den katalytischen Untereinheiten von Selenoproteinen entfaltet. Es wird als Supplement in der Prävention und Therapie einiger Volkskrankheiten wie Autoimmunerkrankungen und Krebs eingesetzt. Die verfügbaren Ergebnisse der klinischen Studien deuten auf geschlechtsspezifische Unterschiede in der Wirksamkeit von Se. Aus diesem Grunde sollte in der vorliegenden Arbeit die Biosynthese von Selenoproteinen in männlichen und weiblichen Mäusen als Modellorganismus für höhere Säugetiere analysiert und verglichen werden. Die gewonnenen Ergebnisse belegen eindeutig, dass die mRNA Konzentrationen von Selenoprotein P, der 5''-Iodothyronin-Deiodase Typ 1 und der extrazellulären Glutathion-Peroxidase 3 geschlechtsspezifische Unterschiede aufweisen. Dieser Dimorphismus ist jedoch nicht konstant, sondern variiert von Gewebe zu Gewebe und zeigt überdies auch eine Abhängigkeit vom Se-Status der Tiere und dem untersuchten Mausstamm. Überraschenderweise korrelieren die resultierenden Proteinmengen nicht linear mit den Unterschieden der mRNA Konzentrationen. Besonders die 5''-Iodothyronin-Deiodase Typ 1 zeigt ausgeprägte Unterschiede in Leber und Niere, wobei sich die Geschlechtsdimorphismen auf mRNA- und Protein-Ebene unterschiedlich stark ausprägen und vom Se-Status beeinflusst werden. Zusammengenommen zeigt diese Arbeit, dass die Expression von Selenoproteinen auf zwei Kontrollebenen geschlechtsspezifisch reguliert wird: über steroidabhängige Gentranskription werden unterschiedliche mRNA Konzentrationen abhängig vom Mausstamm, Alter und Se-Status in den Geweben exprimiert, und über noch nicht eindeutig identifizierte Mechanismen wird die Effektivität, mit der diese Transkripte in die entsprechenden Selenoproteine übersetzt werden, geschlechtsspezifisch kontrolliert. Diese Se-abhängige Regulation der Biosyntheserate, die vermutlich über eine veränderte Translationseffizienz erfolgt, stellt ein sehr überraschendes Ergebnis dar. Sollte es sich in menschlichen Proben bestätigen, so könnten diese Ergebnisse helfen, die geschlechtsspezifischen Befunde in den klinischen Supplementationsstudien zu verstehen und entsprechend abgestimmte Empfehlungen für eine unterschiedliche Supplementation von Mann und Frau zu erarbeiten. / Selenium is an essential trace element and acts as Selenocystein in the catalytic entity of selenoproteins. It is currently in use as supplement in the prevention and therapy of a variety of diseases including autoimmune diseases and cancer. The epidemiological and clinical data indicate that the effectiveness of Se supplementations is sex-specific. Therefore, this thesis was initiated to analyse and compare the expression of selenoproteins in male and female mice as a suitable model organism for higher mammals. The experimental data clearly indicate that selenoprotein P, type I 5'' iodothyronine deiodinase and the secreted glutathione peroxidase 3 display sex-specific differences in mRNA concentrations. The sexual dimorphic expression patterns of these selenoproteins are not constant but depend on the tissue, the Se-status of the animals and the specific mouse strain analysed. Surprisingly, no direct correlation is observed when mRNA levels and expressed protein concentrations are compared. This becomes very obvious in the case of type I 5'' iodothyronine deiodinase in liver and kidney. Both mRNA and protein levels differ between the sexes in a discordant and Se-dependent manner. Taken together, this thesis indicates that selenoprotein expression is regulated in a sex-specific manner by two different mechanisms. First of all, steroid-dependent gene transcription gives rise to sexually dimorphic mRNA levels in the different tissues. Mouse strain, age and Se-status influence this process. Secondly, the sexes differ profoundly with respect to the efficiency of selenoprotein biosynthesis from a given number of transcripts. Presumably, this process involves Se-dependent translational control mechanisms that have not been described before. Under the assumption that these results can be verified with human samples, it is conceivable that this new mechanism might help to explain some of the enigmatic sex-specific effects observed in human supplementary studies and that sex-specific supplementation regimen need to be worked out in the long run.

<p>Spermatogenesen är i många organismer en av de mest dramatiska förvandlingar som en cell kan genomgå – en vanlig, rund, diploid cell omvandlas till en nålformad, haploid cell med ett tätt packat cellmaskineri. I bananfluga, <i>Drosophila melanogaster</i>, innebär denna process flera karaktäristiska stadier. Ett av dessa är det primära spermatocyt-stadiet, som infaller innan cellen påbörjar meios-delning. Stadiet karaktäriseras av en uppluckrad kromatinstruktur i cellens kärna och ovanligt höga transkriptions- och translationshastigheter, för att producera allt det mRNA och de proteiner som behövs senare under spermatidomvandlingen. Två av de proteiner som uttrycks i höga nivåer i primära spermatocyter är ThioredoxinT (TrxT) och Painting of fourth (POF).</p><p>Thioredoxiner är små proteiner som har som funktion att reducera disulfidbryggor i andra proteiner, en mekanism som används i många olika fysiologiska sammanhang. I denna avhandling visar jag att <i>TrxT</i>-genen kodar för ett testikelspecifikt thioredoxin som binder specifikt till Y-kromosom-loopar i primära spermatocyter. <i>TrxT</i>-genen ligger precis bredvid <i>deadhead</i> (<i>dhd</i>), en gen som kodar för ett hon-specifikt thioredoxin som är lokaliserat till cellkärnorna i flugans äggstockar. Ett tredje thioredoxin i <i>Drosophila</i> är det allmänt uttryckta Thioredoxin-2 (Trx-2). Jag har upptäckt att flugor som saknar Trx-2 är livsdugliga, men att de lever kortare än vildtypsflugor, medan flugor med extra mycket Trx-2 har en ökad tålighet mot oxidativ stress. Slående nog är en total avsaknad av alla tre thioredoxiner inte förenat med letalitet, tvärtemot vad man skulle kunnat vänta sig. Alla tre thioredoxiner finns i de olika <i>Drosophilider</i> som undersökts och den ovanliga genorganisation som delas av <i>TrxT</i> och <i>dhd</i> är generellt konserverad.</p><p>Gen-namnet <i>Painting of fourth</i> härstammar från upptäckten att POF binder till (”målar”) <i>Drosophilas</i> kromosom 4. Jag visar i min avhandling att POFs bindning till den fjärde kromosomen är bevarad i olika <i>Drosophila</i>-arter och att POF kolokaliserar med både ett protein och en histon-modifiering, som är förknippade med doskompensation, i arter där POF också binder till hanens X-kromosom. POF uttrycks överallt i både honor och hanar, men i väldigt höga nivåer i hanens testiklar. Jag visar här att POF finns i cellkärnan hos primära spermatocyter, men också i kärnan på mognande spermatider, och att avsaknad av POF in hanens könsceller orsakar en global nedreglering av gener som ligger på kromosom 4. Kombinationen av mina POF- resultat tyder på att POF har en viktig funktion i det första kända fallet av genreglering av en hel autosomal kromosom.</p> / <p>The process of spermatogenesis is in many organisms one of the most dramatic cellular transformations - a normal round diploid cell is ultimately transformed into a needle shaped haploid cell with tightly packaged cell machinery. In <i>Drosophila melanogaster</i> this process involves several characteristic stages, one of these being the primary spermato-cyte stage, which is the stage prior to meiosis. This stage is characterized by a loose chromatin structure in the nucleus and exceptionally high rates of transcription and translation to produce essentially all the mRNAs and proteins that are needed later during spermatid formation. Two proteins that are expressed in high levels in primary spermatocytes are ThioredoxinT (TrxT) and Painting of fourth (POF).</p><p>Thioredoxins are small thiol proteins that reduce disulfides in other proteins, a mechanism that is utilized in many different contexts. In this thesis I show that the <i>TrxT</i> gene encodes a testis-specific thioredoxin that specifically associates to Y-chromosome loops in primary spermatocytes. <i>TrxT</i> is located right next to <i>deadhead</i> (<i>dhd</i>), a gene that encodes a female-specific thioredoxin that specifically locates to nuclei in the ovaries. A third thioredoxin in <i>Drosophila</i> is the ubiquitously expressed Thioredoxin-2 (Trx-2). I have found that flies lacking Trx-2 are viable but have shorter life spans than wild type flies, while over-expression of Trx-2 mediates an increased resistance to oxidative stress. Interestingly, a lack of all three thioredoxins does not result in lethality, contrary to what could be expected. All three thioredoxins are conserved among <i>Drosophilids</i> and the striking genomic organization of <i>TrxT</i> and <i>dhd</i> is generally conserved.</p><p>The gene name <i>Painting of fourth</i> originates from the finding that POF stains the 4th chromosome of <i>Drosophila</i> in a banded pattern on salivary gland chromosomes. I show in this thesis that POF binding to the equivalent of the 4th chromosome is conserved in genus <i>Drosophila</i> and that POF co-localizes with both a protein and a histone modification associated with dosage compensation in species where POF also binds the male X. POF is expressed ubiquitously in both males and females, but at very high levels in male testes. I show that POF is present in nuclei of primary spermatocytes, but also in nuclei of maturing spermatids and that a lack of POF in the male germline causes a global down-regulation of chromosome 4 genes. These results combined suggest a function of POF in the first known case of chromosome-wide gene regulation of an autosome.</p>

Spermatogenesen är i många organismer en av de mest dramatiska förvandlingar som en cell kan genomgå – en vanlig, rund, diploid cell omvandlas till en nålformad, haploid cell med ett tätt packat cellmaskineri. I bananfluga, Drosophila melanogaster, innebär denna process flera karaktäristiska stadier. Ett av dessa är det primära spermatocyt-stadiet, som infaller innan cellen påbörjar meios-delning. Stadiet karaktäriseras av en uppluckrad kromatinstruktur i cellens kärna och ovanligt höga transkriptions- och translationshastigheter, för att producera allt det mRNA och de proteiner som behövs senare under spermatidomvandlingen. Två av de proteiner som uttrycks i höga nivåer i primära spermatocyter är ThioredoxinT (TrxT) och Painting of fourth (POF). Thioredoxiner är små proteiner som har som funktion att reducera disulfidbryggor i andra proteiner, en mekanism som används i många olika fysiologiska sammanhang. I denna avhandling visar jag att TrxT-genen kodar för ett testikelspecifikt thioredoxin som binder specifikt till Y-kromosom-loopar i primära spermatocyter. TrxT-genen ligger precis bredvid deadhead (dhd), en gen som kodar för ett hon-specifikt thioredoxin som är lokaliserat till cellkärnorna i flugans äggstockar. Ett tredje thioredoxin i Drosophila är det allmänt uttryckta Thioredoxin-2 (Trx-2). Jag har upptäckt att flugor som saknar Trx-2 är livsdugliga, men att de lever kortare än vildtypsflugor, medan flugor med extra mycket Trx-2 har en ökad tålighet mot oxidativ stress. Slående nog är en total avsaknad av alla tre thioredoxiner inte förenat med letalitet, tvärtemot vad man skulle kunnat vänta sig. Alla tre thioredoxiner finns i de olika Drosophilider som undersökts och den ovanliga genorganisation som delas av TrxT och dhd är generellt konserverad. Gen-namnet Painting of fourth härstammar från upptäckten att POF binder till (”målar”) Drosophilas kromosom 4. Jag visar i min avhandling att POFs bindning till den fjärde kromosomen är bevarad i olika Drosophila-arter och att POF kolokaliserar med både ett protein och en histon-modifiering, som är förknippade med doskompensation, i arter där POF också binder till hanens X-kromosom. POF uttrycks överallt i både honor och hanar, men i väldigt höga nivåer i hanens testiklar. Jag visar här att POF finns i cellkärnan hos primära spermatocyter, men också i kärnan på mognande spermatider, och att avsaknad av POF in hanens könsceller orsakar en global nedreglering av gener som ligger på kromosom 4. Kombinationen av mina POF- resultat tyder på att POF har en viktig funktion i det första kända fallet av genreglering av en hel autosomal kromosom. / The process of spermatogenesis is in many organisms one of the most dramatic cellular transformations - a normal round diploid cell is ultimately transformed into a needle shaped haploid cell with tightly packaged cell machinery. In Drosophila melanogaster this process involves several characteristic stages, one of these being the primary spermato-cyte stage, which is the stage prior to meiosis. This stage is characterized by a loose chromatin structure in the nucleus and exceptionally high rates of transcription and translation to produce essentially all the mRNAs and proteins that are needed later during spermatid formation. Two proteins that are expressed in high levels in primary spermatocytes are ThioredoxinT (TrxT) and Painting of fourth (POF). Thioredoxins are small thiol proteins that reduce disulfides in other proteins, a mechanism that is utilized in many different contexts. In this thesis I show that the TrxT gene encodes a testis-specific thioredoxin that specifically associates to Y-chromosome loops in primary spermatocytes. TrxT is located right next to deadhead (dhd), a gene that encodes a female-specific thioredoxin that specifically locates to nuclei in the ovaries. A third thioredoxin in Drosophila is the ubiquitously expressed Thioredoxin-2 (Trx-2). I have found that flies lacking Trx-2 are viable but have shorter life spans than wild type flies, while over-expression of Trx-2 mediates an increased resistance to oxidative stress. Interestingly, a lack of all three thioredoxins does not result in lethality, contrary to what could be expected. All three thioredoxins are conserved among Drosophilids and the striking genomic organization of TrxT and dhd is generally conserved. The gene name Painting of fourth originates from the finding that POF stains the 4th chromosome of Drosophila in a banded pattern on salivary gland chromosomes. I show in this thesis that POF binding to the equivalent of the 4th chromosome is conserved in genus Drosophila and that POF co-localizes with both a protein and a histone modification associated with dosage compensation in species where POF also binds the male X. POF is expressed ubiquitously in both males and females, but at very high levels in male testes. I show that POF is present in nuclei of primary spermatocytes, but also in nuclei of maturing spermatids and that a lack of POF in the male germline causes a global down-regulation of chromosome 4 genes. These results combined suggest a function of POF in the first known case of chromosome-wide gene regulation of an autosome.

Hermaphroditism, associated with territoriality and dominance behavior, is common in the marine environment. Male sex-specific coloration patterns and behavior are particularly evident in species where males are territorial and guard harems of females such as wrasses and groupers. Protogynous hermaphrodites that change sex from female to male are good models to study sexual behavior and related changes in the brain due to their abilities to reorganize their sexual phenotype as adults. Two hormones produced in the brain and implicated in the process of sex-specific behavior and reproductive development are arginine vasotocin (AVT) and gonadotropin releasing hormone (GnRH). While a wealth of data exists regarding these hormone systems separately, little is known about linkage between these two systems. Especially there is no data tracking these two systems together in any protogynous fish. This study was conducted to test the hypothesis that coordinated interactions between AVT and GnRH facilitate the process of behavioral and gonadal sex change in the rock hind Epinephelus adscensionis. Four topics were addressed to investigate the relationship between behavior and reproduction: i) rock hind sex change, sexual characteristics and conditions causing sex change to occur in captivity were detailed as a basis for examining the AVT system and GnRH during this process, ii) the distribution of a vasotocin V1a type receptor identified in rock hind brain was examined for the first time in a fish species using a custom designed antibody then the receptor protein was co-localized with GnRH producing cells within the brain to confirm that a pathway exists for AVT action on GnRH, iii) levels of AVT, AVT receptors, and GnRH messenger RNA (mRNA) were compared between male and female rock hind phenotypes, and iv) female rock hind at early stages of sex change were compared for brain mRNA expression of AVT, AVT receptors, and GnRH to determine the order of hormonal change during the process of sexual inversion in this species. This study provides a better understanding of the relationship between sex-specific behavior and reproductive development via AVT and GnRH systems that are conserved in all vertebrates. / text

Osteoarthritis is a degenerative joint disease characterized by progressive erosion of the articular cartilage. Epidemiological studies have established a relationship between osteoarthritis and menopause suggesting that estrogen may be important in the development of cartilage regeneration therapies. The overall goal of this research project was to advance the field of cartilage tissue regeneration by investigating the role of 17 ß -estradiol (E2), an active estrogen metabolite, on the chondrocyte phenotype. The central hypothesis was that E2 plays an important and sex-specific role in regulating chondrogenesis. Specific Aim-1 focused on establishing and characterizing a primary human articular chondrocyte (HAC) cell source, and then examining the response of the cells in culture to E2. It was demonstrated that the response of HACs to E2 treatment was sex-specific despite both male and females cells expressing estrogen receptors. Female HACs showed changes in proliferation, matrix production, and differentiation while male cells did not. In addition, the female response was regulated through a rapid membrane signaling pathway mediated by protein kinase C. Specific Aim-2 involved establishing an ovariectomized animal model to investigate the effects of E2 on orthopaedic tissue implants. Human demineralized bone matrix (DBM) was implanted intramuscularly into female nude mice and rats. Ovariectomy was shown to reduce the ability of DBM to induce the formation of cartilage and bone tissue. Moreover, the inductive properties of DBM were reestablished with subcutaneous E2 supplementation. Specific Aim-3 entailed developing and characterizing a microencapsulation method for in vitro culture and in vivo delivery of chondrocytes to study the effects of E2 on chondrogenesis. Rat growth plate chondrocytes and HACs were microencapsulated in alginate using an extrusion method in conjunction with high electrostatic potential. Chondrocytes maintained their phenotype in alginate suspension but were unable to form cartilage tissue when implanted into our animal model. Further optimization of the system is required before the role of E2 on chondrogenesis of tissue engineered constructs can be determined. In summary, our results suggest that the successful production of tissue engineered therapies will likely depend on understanding and manipulating the actions of sex hormones in both the in vitro and in vivo environment.

<p> This research examined the geographic variability as well as the individual-and neighbourhood-level determinants of overweight and obesity in Canada. Overweight and obesity represent a significant public health problem with grave implications for individuals as well as populations. Over the past two decades, the prevalence of overweight and obesity has reached epidemic proportions with the most substantial increases observed in economically developed countries. The World Health Organization indicated that globally 1.6 billion adults (age 15+) are overweight and at least 400 million adults were obese. In a Canadian context, recent data from Statistics Canada confirms that over the past twenty-five years, adult obesity rates in Canada have doubled (23% ), while childhood obesity rates have nearly tripled. </p> <p> Until recently, research has focused on biological and behavioural determinants of obesity, and currently there is a great deal of knowledge regarding the relationships between weight status and various risk factors at the individual-level (e.g. age, sex, socioeconomic deprivation, diet, physical activity). However, the majority of existing research has ignored the potential role played by the environment in the development of these conditions, despite a growing consensus that environmental and/or societal constraints may be major influences on increasing prevalence rates. </p> <p> Using data from the Canadian Community Health Surveys and the Desktop Mapping Information Technologies Incorporated spatial database, this research addressed the following objectives: (I) to examine sex-specific spatial patterns of overweight/obesity in Canada as well as investigate the presence of spatial clusters (2) to investigate the prevalence and determinants of overweight and obesity in Canada using spatial analysis and geographical information systems (GIS) and (3) to identify heterogeneities associated with the relationships between individual and socioenvironmental determinants and overweight and obesity at the individual-and community-levels. </p> <p> Results revealed marked geographical variation in overweight/obesity prevalence with higher values in the Northern and Atlantic health-regions and lower values in the Southern and Western health-regions of Canada. Significant positive spatial autocorrelation was found for both males and females, with significant clusters of high values or 'hot spots' of obesity in the Atlantic and Northern health-regions of Alberta, Saskatchewan, Manitoba and Ontario. Results also demonstrate the important role of the built-environment after adjustment demographic, socio-economic and behavioural characteristics. With regard to the built environment measures, landuse mix and residential density were found to be significantly associated with BMI. This study also demonstrated significant differences at the area-level of analysis, supporting related research that has suggested that individual-level factors alone cannot explain variation in obesity rates across space. In particular, average dwelling value was related to BMI independently of individual-level characteristics. Ultimately, this research has demonstrated that Canadian urban environments play a small but significant role in shaping the distribution of BMI. Yet, reversing current trends will require a multifaceted public health approach where interventions are developed from the individual-to the neighbourhood-level, specifically focusing on altering obesogenic environments. </p> / Thesis / Doctor of Philosophy (PhD)