Abstract Non-pathological change in body weight and adiposity is one distinct adaptive feature that seasonal species undergo, and it can offer a novel way to study the mechanisms underlying body weight regulation and energy homeostasis. Changes in the expression and activity of metabolic enzymes are essential for the physiological adaptation seasonal species exhibit. AMP-activated protein kinase (AMPK) is a key regulatory enzyme that controls the energy homeostasis both on cellular and whole-body level. In this thesis, the main focus was to clarify how seasonal adaptation affects AMPK and its downstream target in lipid metabolism, acetyl-CoA carboxylase (ACC), in different metabolic tissues of two model species with diverse wintering strategies: the raccoon dog and the Djungarian hamster. In addition, the effect of periodic fasting on the raccoon dog skeletal muscle was studied. It was observed that seasonal differences in AMPK and ACC expression were evident mainly in adipose tissues of both species. AMPK was down-regulated in white adipose tissue (WAT) of the winter-adapted raccoon dog, whereas in the Djungarian hamster WAT, the abundance of AMPK increased in response to winter acclimatization. ACC expression was maintained or increased in winter in both species. The seasonal changes in AMPK and ACC expression observed, in particular, in adipose tissues reflects the wintering strategy of the species and presumably facilitates the lipid usage and/or preservation during wintertime scarcity. Raccoon dogs were quite resistant to the prolonged wintertime fast, as no changes were observed in AMPK and ACC expression levels in the WAT, liver or hypothalamus between the fasted and fed groups. Skeletal muscle function also appears to be well preserved, as there were no changes in the expression of proteins involved in insulin signaling, and the fiber type composition and muscle energy reserves were not affected. This thesis offers novel information on protein level changes in metabolic adaptation. / Tiivistelmä Useat luonnonvaraiset eläinlajit ovat fysiologisesti sopeutuneet ravinnonsaannin vuodenaikaisiin vaihteluihin. Vuodenaikaisrytmiin kytketty rasvakudoksen määrän vaihtelu ja siihen liittyvät aineenvaihdunnalliset muutokset tarjoavat mielenkiintoisen tutkimuskohteen ruumiinpainon säätelyn ja energiatasapainon ylläpidon molekulaaristen mekanismien selvittämiseen. Oleellinen osa fysiologista sopeutumista ovat muutokset energia-aineenvaihduntaa säätelevien proteiinien ekspressio- ja aktiivisuustasoissa. Yksi keskeinen elimistön energiatasapainoa kontrolloiva entsyymi on AMP-aktivoituva proteiinikinaasi (AMPK). AMPK toimii solunsisäisenä energiasensorina ja säätelee energiametaboliaa koko kehon tasolla. Tässä väitöskirjatutkimuksessa selvitettiin talviadaptaation vaikutusta AMPK:n ja sen kohdemolekyylin, rasvahappojen biosynteesiä säätelevän asetyyli-CoA karboksylaasin (ACC), ilmenemiseen ja aktiivisuuteen eri kudoksissa. Mallieläiminä käytettiin kahta eri talvehtimisstrategian omaavaa ja eri lailla ruumiinpainoaan säätelevää lajia, kääpiöhamsteria ja supikoiraa. Lisäksi tutkittiin pitkäaikaisen talvipaaston vaikutusta supikoiran luustolihakseen. Tulokset osoittivat, että molemmilla lajeilla AMPK- ja ACC-pitoisuuksissa on vuodenaikaisia eroja erityisesti rasvakudoksessa. Supikoiralla AMPK:n määrä väheni talviadaptaation seurauksena, kun taas kääpiöhamstereilla talviakklimatisaatio johti korkeampaan AMPK-pitoisuuteen rasvakudoksissa. ACC-pitoisuus puolestaan säilyi samana tai oli korkeampi talviadaptoituneilla yksilöillä. Havaitut muutokset AMPK:n ja ACC:n ilmenemisessä kuvastavat supikoiran ja kääpiöhamsterin eroja talvehtimisessa ja havainnollistavat entsyymien oleellista osaa rasvavarastojen vuodenaikaisessa säätelyssä ja käytössä, mikä on edellytys eläinten selviämiselle yli talven niukkuuden. Lisäksi havaittiin talviadaptoituneen supikoiran olevan melko resistentti 10 viikon paastolle tutkittujen parametrien suhteen. AMPK- ja ACC-pitoisuus tai aktiivisuus ei muuttunut aineenvaihdunnallisesti oleellisissa kudoksissa (rasvakudos, maksa, hypotalamus) paasto- ja kontrolliryhmän välillä. Supikoiran lihasten toimintakyky vaikuttaisi säilyvän, sillä insuliinisignalointiin liittyvien entsyymien pitoisuus, lihasten solutyyppikoostumus tai energiavarastot eivät muuttuneet paaston myötä. Tämä tutkimus tarjoaa uutta tietoa proteiinitason muutoksista osana fysiologista sopeutumista.

Despite the importance of muscle in the development of type 2 diabetes, few studies have investigated the effect of polychlorinated biphenyls (PCBs) on muscle energy metabolism. Previous results from our lab suggested that PCB126 exposure induced an indirect negative effect on muscle mitochondrial function. Since PCBs are stored in adipose tissue, we hypothesized that PCB126 alters adipokine secretion which in turn affects muscle metabolism. Objectives. Study the adipose-to-muscle communication in PCB126-induced metabolic defects. Methods. Communication between adipocytes and myotubes was reproduced by exposing C2C12 or mouse primary myotubes to the conditioned medium (CM) of 3T3L1 adipocytes exposed to environmentally relevant PCB126 levels. Results. PCB126 significantly increased adipokine secretion and decreased mitochondrial function, glucose uptake and glycolysis in insulin resistant (IR) but not in insulin sensitive 3T3L1. However, exposure of myotubes to CM of IR 3T3L1 only decreased glucose uptake and insulin sensitivity, without altering myotubes glycolysis or mitochondrial function. Conclusion. Our results suggest that the increased adipokine secretion by adipocytes could explain the decreased muscle glucose uptake and insulin sensitivity when exposed to PCB126.

Obesity is associated with dysfunction of adipose tissue due to oxidative stress and inflammation, leading to insulin resistance. Thiosulfate sulfurtransferase (Tst) was previously identified as an adipose-expressed anti-diabetic gene that protects against diet-induced metabolic impairment when upregulated in adipose tissue of mice. TST is a mitochondrial enzyme involved in the metabolism of cyanide, reactive oxygen species (ROS) and endogenous hydrogen sulfide (H2S). This thesis tested the hypothesis that TST maintains metabolic health in the face of dietary obesity. To do this, I investigated the adipose-tissue phenotypes and metabolic consequences of Tst gene deletion (Tst–/– mice) and of adipose tissue-specific overexpression of human TST (Ad-hTST mice) after exposure to high fat diet (HFD). After 20 weeks of HFD, Tst–/– mice exhibited impaired glucose tolerance despite unchanged adipose tissue inflammatory cell infiltration, protein carbonylation and unfolded protein response activation. However, levels of mRNA encoding mitochondrial antioxidant enzymes including superoxide dismutase 2 and peroxiredoxin 3 were lower in Tst–/– mice on HFD. Unexpectedly, chow-fed Tst-/- mice had lower body weight and fat mass than wild-type controls highlighting a potential effect of Tst on fat accumulation with age. A new mouse model with high expression of human TST genetically targeted to adipose tissue (Ad-hTST) was developed using the LoxP / Cre recombinase expression system, with a parent line expressing Cre under the control of the adiponectin promoter to confer adipose specificity. The Ad-hTST mice were found to gain a similar amount of weight and fat mass to control mice when exposed to 6 weeks of HFD. However, Ad-hTST mice had impaired glucose tolerance with no change in inflammatory cell infiltration, mRNA levels of antioxidant enzymes or unfolded protein response genes. Thus, unexpectedly, overexpression of human TST in adipose tissue of mice results in a detrimental metabolic phenotype. In vivo and in vitro experiments were conducted to test the hypothesis that TST protects against ROS accumulation. Paraquat was tested as an inducer of oxidative stress in vivo in wild-type, Tst-/- and Tst+/- mice. At the doses used (25mg/kg and under), mice became unwell and lost weight, with no increase in markers of oxidative stress in adipose or lung. The production of mitochondrial ROS in response to exogenous hydrogen peroxide (H2O2) exposure was increased in primary adipocytes from Tst-/- mice in vitro. However, primary hepatocytes showed reduced mitochondrial ROS production in response to H2O2 exposure. ROS production in hepatocytes was unaffected by pre-incubation with a H2S donor, an inhibitor of H2S-producing enzyme CSE or N-acetyl-cysteine, an antioxidant. TST may therefore influence mitochondrial ROS production differently in cell types such as adipocytes and hepatocytes. Disposal of exogenous H2O2 was unchanged in primary adipocytes from Tst-/- and Ad-hTST mice, and this was not affected by pre-incubation with sodium thiosulfate, a TST substrate. Metabolic changes in response to HFD may be influenced by alteration in TST expression, however the current data suggest it is unlikely to occur through the prevention of excessive local ROS accumulation in adipose tissue. Mice lacking the Tst gene globally and mice with adipose-specific overexpression of the human TST gene have a similarly impaired metabolic response to HFD. The phenotype of adipose-specific human TST-overexpressing mice does not recapitulate the protective metabolic phenotype produced by overexpression of the endogenous mouse Tst gene. In conclusion, TST may influence adipose tissue due to its role in the oxidation of H2S, however, by the current means, it does not appear to substantially impact the response of this tissue to oxidative stress.

Introdução: Ao ser usado o retalho de omento dissecado por videolaparoscopia no tratamento de deformidades da mama, foi constatado um significativo aumento do seu volume nos primeiros meses após a sua transposição, em todas as pacientes operadas, o que não é visto com essa magnitude em nenhum outro retalho adiposo. Métodos: Para se estudar o motivo desse aumento de volume, foram realizados estudos histológicos de amostras de omento coletadas no primeiro tempo cirúrgico, logo após sua transposição da cavidade abdominal para a região mamária e, no segundo tempo cirúrgico, durante a complementação de tratamento para a simetrização das mamas de oito pacientes. Foram documentadas as modificações nas medidas morfométricas dos adipócitos (perímetro, diâmetro e área), na densidade microvascular mediante o marcador endotelial CD31 e na expressão imunohistoquímica do fator de crescimento do endotélio vascular (VEGF). Resultados: O aumento do tamanho dos adipócitos e da densidade microvascular foi estatisticamente significativo (P≤0,012). O valor do VEGF foi menor na segunda amostra em relação com a primeira, redução esta que não atingiu significância considerável (P<0,093). Conclusão: Estes resultados sinalizam um aumento no volume celular que se mostrou consistente quando foram utilizados três diferentes processos de medida: perímetro, diâmetro e área dos adipócitos. Além disso, o aumento do número de vasos na segunda amostra sugere que tenha ocorrido neoangiogênese estimulada pelo aumento inicial dos valores do VEGF. Portanto o aumento do volume do retalho se deve a neovascularização e hipertrofia do adipócito. / Introduction: When laparoscopically harvested omentum flap was used to treat breast deformities, a significant volume increase, which had never been noticed in any other adipose flap, was observed in all the patients in the first months following its transposition. Methods: Histological studies of omentum samples were performed to study the reason for this increase. Samples were harvested at the first surgical time, right after the transposition of the omentum from the abdominal cavity to the breast region, and at the second surgical time, during treatment complementation for breast symmetrization of eight patients submitted to the transposition of the omentum flap. Modifications in the morphometric measurements of the adipocytes (perimeter, diameter, and area), in the microvascular density by the CD31 endothelial marker and in the imunohistochemic expression of VEGF were documented. Results: the increase in adipocyte size and microvascular density was statistically significant (P≤0.012). The value of VEGF was lower in the second sample, which was not significant (P<0.093). Conclusion: These results suggest an increase in cellular volume that was consistent when three different measurement procedures were used: adipocyte perimeter, diameter, and area. Moreover, the increase in the number of vessels in the second sample suggests neoangiogenesis stimulated by the initial increase in VEGF values obtained in the first sample. The flap increase was probably caused by adipocyte hypertrophy, resulting from the neoangiogenesis.

Submitted by Diogo Misoguti (diogo.misoguti@gmail.com) on 2016-07-07T18:49:46Z No. of bitstreams: 1 cp078451.pdf: 1963747 bytes, checksum: 8df763273b9205acc5055fd0cbc3d714 (MD5) / Approved for entry into archive by Diogo Misoguti (diogo.misoguti@gmail.com) on 2016-07-07T18:50:39Z (GMT) No. of bitstreams: 1 cp078451.pdf: 1963747 bytes, checksum: 8df763273b9205acc5055fd0cbc3d714 (MD5) / Made available in DSpace on 2016-07-07T18:50:39Z (GMT). No. of bitstreams: 1 cp078451.pdf: 1963747 bytes, checksum: 8df763273b9205acc5055fd0cbc3d714 (MD5) Previous issue date: 2008 / Objetivo: Avaliar, do ponto de vista histológico, o efeito do transplante de tecido adiposo sobre o útero e os ovários de camundongas obesas e anovuladoras. Métodos: Foram utilizadas camundongas B6.V-Lepob/J com 2 e 3 meses de idade, subdivididas em grupos experimentais: 1.Controle (B6.V-Lepob/J fêmeas, com peso normal); 2.Obesidade (B6.V-Lepob/J fêmeas, obesas); 3.Obesidade + Transplante de tecido adiposo de camundongas doadoras com peso normal após 7 dias (B6.V-Lepob/J fêmeas e obesas, que receberam aproximadamente 1g de tecido adiposo de camundongas com peso normal isogênicas); 4.Obesidade + Transplante de tecido adiposo de camundongas doadoras com peso normal após 15 dias (B6.V-Lepob/J fêmeas e obesas, que receberam aproximadamente 1g de tecido adiposo de camundongas com peso normal isogênicas); 5.Obesidade + Transplante de tecido adiposo de camundongas doadoras com peso normal após 45 dias (B6.V-Lepob/J fêmeas e obesas, que receberam aproximadamente 1g de tecido adiposo de camundongas com peso normal isogênicas). Após 7, 15 e 45 dias do transplante, os animais foram sacrificados. Foram verificados o peso corporal e a glicemia, além da análise histológica dos úteros e dos ovários (H/E). Resultados e Conclusões: O grupo das obesas (n=6) apresentou elevação no peso corporal (52,0± 1,3*) e na glicemia (418,4±33,0*) em relação ao controle (24,0±0,7 e 100,2±2,2, respectivamente, n=5). Os transplantes após 7 dias (n=5) e 15 dias (n=9) foram eficazes na redução da glicemia (390,2±34,0 e 270,0±38,0*, pré e pós-Tx 7 dias; e 460,0±31,4 e 125,0±8,4*, pré e pós-Tx 15 dias, respectivamente), mas não modificaram o peso corporal. Porém, após 45 dias de transplante (n=7) houve redução da glicemia (467,0±28,0 e 209,0±18,0*, pré e pós-Tx, respectivamente), assim como tendência à diminuição no peso corpóreo observado pré e pós-Tx (50,4±2,4 e 44,0±3,3). Valores adotados para *p< 0,0001. A histologia revelou que, após 7 e 15 dias de Tx, os animais apresentavam ovários semelhantes aos das obesas, incluindo presença de inúmeros folículos, interstício abundante e ausência de corpos lúteos. Nos úteros notou-se intensa estimulação hormonal e glandular, mitoses, raros eosinófilos e epitélio superficial íntegro e sem renovação, sugerindo que tempos precoces de Tx são incapazes de reverter tais alterações. Entretanto, no grupo Tx 45 dias foram visualizados úteros praticamente iguais aos do controle, com grande número de leucócitos e remodelação do epitélio superficial, além de ovários com reduzida quantidade de folículos e presença de corpos lúteos, indicando ovulação. As camundongas B6.V-Lepob/J obesas apresentam formações polimicrocísticas e estroma abundante, mimetizando os achados ovarianos das pacientes anovuladoras. O Tx de tecido adiposo, a longo prazo, parece ter papel na diminuição da obesidade, mostrando-se eficiente na reversão da hiperglicemia e das alterações ovarianas e uterinas, presentes nas camundongas obesas, restabelecendo a ovulação. / Objective: To assess from the histological point of view the effect of adipose tissue transplantation onto the uterus and ovaries of obese, anovulating mice.en Method: B6.V-Lepob/J mice were used and the following experimental groups evaluated: 1.Control group (B6.V-Lepob/J female, average weight); 2.Obesity (B6.V-Lepob/J female, obese); 3.Obesity plus adipose tissue transplant from mice donors which were average weight after 7 days (B6.V-Lepob/J obese females which received adipose tissue from thin, isogenic mice); 4.Obesity plus adipose tissue transplant from mice donors which were average weight after 15 (B6.V-Lepob/J obese females which received adipose tissue from thin, isogenic mice); 5.Obesity plus adipose tissue transplant from mice donors which were average weight after 45 days (B6.V-Lepob/J obese females which received adipose tissue from thin, isogenic mice);. Within 7, 15 and 45 days of the transplant the animals were sacrificed. The age range was between 2 and 3 months old. In addition to the histological analyses of uteri and ovaries (H/E), these animals’ corporal weight and glycemia were verified. Results and Conclusion: The obese group (n=6) presented with elevation in corporal weight (52,0 ± 1,3*)and glycemia (418,4± 33,0*) in relation to the control group (24,0 ± 0,7 and 100,2± 2,2 respectively, n=5). The transplants after 7 days (n=5) and 15 days (n=9) were effective in reducing glycemia (390,2 ± 34,0 and 270,0 ± 38,0*, 7 days pre and post transplant; and 460,0 ± 31,4 and 125,0 ± 8,4*, 15 days pre and post transplant respectively), but not in changing corporal weight. However, within 45 days of the transplant (n=7) there was a reduction in glycemia (467,0 ± 28,0 and 209,0 ± 18,0*, pre and post- transplant respectively), as well as a tendency to reduce corporal weight observed pre and post transplant (50,4 ±2,4 and 44,0 ± 3,3). Values used for *p< 0,0001. Histology revealed that within 7 and 15 days of the transplant, the animals presented with ovaries similar to those in the obese group, containing countless follicles, abundant interstice and absence of corpora lutea. The uteri revealed intense hormonal and glandular stimulation, mitosis, scarse eosinophils and the superficial epithelium whole, without renovation, indicative of the inability of short term transplantations to reverse such alterations. In the 45-day-group, however, the uteri looked very much the same as those of the control group, with a great number of leucocytes and remodellation of the superficial epithelium, as well as ovaries with a reduced amount of follicles and presence of corpora lutea, suggesting ovulation. The obese B6.V-Lepob/J mice present with polymicrocystic formation and abundant oestrone, mimicking the ovarian findings of the anovulating patients. The long term adipose tissue transplantation, on the other hand, seems to play a part in reducing obesity, proving to be efficient in reversing hypoglycemia and the ovarian and uterine alterations present in obese mice, re-establishing ovulation

Le développement du tissu adipeux blanc est finement régulé par des facteurs pro- et anti- adipogéniques. Au cours de l’obésité, son expansion conduit à de nombreuses complications métaboliques. A ce jour, peu de données sont disponibles sur les facteurs qui contrôlent négativement son développement. Dans ce contexte, le laboratoire a dirigé ses recherches sur le rôle de l’aldose réductase murine Akr1b7 dans ce tissu. Akr1b7 est exprimée dans la fraction stromale vasculaire du tissu adipeux blanc et possède un effet anti-adipogénique sur les préadipocytes en culture. La réalisation et l’analyse de souris invalidées pour le gène Akr1b7 nous a permis de démontrer que la perte de Akr1b7 entraîne une expansion de la masse adipeuse par une hypertrophie et une hyperplasie des adipocytes associées à une insulino-résistance. Les souris Akr1b7-/- ne sont pas hyperphagiques mais présentent un métabolisme basal réduit. Akr1b7 qui possède une activité prostaglandine synthase, régule le développement excessif du tissu adipeux par deux mécanismes dépendant de la PGF2α à savoir, l’inhibition de l’adipogenèse et de la lipogenèse. D’autre part, nous avons développé un modèle de souris transgéniques sur-exprimant l’aldose réductase humaine AKR1B1 dans le tissu adipeux. Contre toute attente et à l’inverse de Akr1b7, ce modèle montre un effet pro-adipogénique deAKR1B1. Ces données in vivo révèlent des activités inédites et opposées entre différentes isoformes d’aldose réductase et ouvrent de nouvelles pistes pour appréhender les mécanismes contrôlant l’homéostasie adipeuse et ses dérèglements. / White adipose tissue development is tightly regulated by pro-and anti-adipogenic factors. In obesity, its increased development leads to many metabolic complications. To date, little is known about the factors that control negatively its growth. In this context, the laboratory has focused researches on the murine aldose reductase Akr1b7 role in white adipose tissue. Akr1b7 is expressed in stromal vascular fraction of white adipose tissue and exhibits an anti-adipogenic action on a preadipocyte cell line. Generation and study of Akr1b7-/- knockout mice allows us to demonstrate that lack of Akr1b7 leads to adipose tissue expansion due to hypertrophy and hyperplasia of adipose cells associated to insulin resistance. Akr1b7-/- mice are not hyperphagic but show reduced basal metabolic rate. This phenotype confirms Akr1b7 involvement in adipose tissue physiology. Akr1b7 regulates development of adipose tissue by a PGF2α-dependent inhibition of both adipogenesis and lipogenesis. On the other hand, we have developed a transgenic murine model over-expressing the human aldose reductase AKR1B1 in adipose tissue. Against all odds and contrary to Akr1b7, this model shows a pro-adipogenic effect of AKR1B1. These in vivo data reveal new and opposed activities of different aldose reductase isoforms and open new avenues to understand the mecanisms regulating fat homeostasis and its disturbances.

Os níveis de obesidade vêm aumentando, no Brasil e no mundo, de maneira exponencial. A condição de excesso de tecido adiposo pode gerar um prejuízo funcional, bem como alterações em uma série de parâmetros de saúde cardiovascular. A quantidade e qualidade muscular apresentada por um indivíduo obeso podem ser determinantes na maneira como o organismo lida com esses desafios. Dessa forma, o objetivo do presente estudo foi verificar a existência de associação entre variáveis de força, qualidade e quantidade muscular, funcionalidade, saúde vascular e adiposidade em indivíduos obesos. Para isso, trinta e quatro indivíduos obesos, com idade entre 20-60 anos, sedentários, não fumantes e não diabéticos, se voluntariaram a participar do estudo. Após prévia familiarização, foram realizados testes de força nos extensores de joelho (contração isométrica voluntária máxima - CIVM ; 1 repetição máxima - 1RM; potência média) e funcionalidade (teste de caminhada de 6 minutos - TC6M; sentar e levantar em 30 segundos - SL30; get up and go). A massa muscular (EMQUA) e echo intensity do quadríceps femoral (EIQUA) foram medidas por ultrassonografia, bem como diferentes parâmetros de adiposidade e função endotelial (avaliada por dilatação mediada por fluxo - DMF). Foram verificados os coeficientes de correlação de pearson entre as variáveis acima citadas e adotou-se um p<0.05 para associação significativa. Foi encontrada uma associação negativa significativa entre a EIQUA e todos os testes de força analisados, bem como com os testes funcionais. A EMQUA também apresentou correlação significativa, porém positiva, com os testes de força e funcionalidade. A EIQUA apresentou uma associação significativa com a gordura visceral, bem como com a gordura subcutânea da coxa. Além disso, a gordura subcutânea abdominal apresentou associação significativa com a DMF. Os dados do presente estudo mostraram haver uma associação significativa entre a quantidade e qualidade muscular e o desempenho em testes de força e funcionais em indivíduos obesos. Ainda, importantes parâmetros de adiposidade se correlacionaram com a EIQUA e com a DMF, um importante marcador de saúde endotelial. Dessa forma, estartégias de intervenção (por exemplo, treinamento de força), que sejam capazes de modificar os parâmetros acima descritos, devem ser priorizadas quando o objetivo for uma melhora na qualidade de vida de indivíduos obesos. / Obesity levels are increasing in Brazil and all over the world in an exponential way. The adipose tissue excess may affect functionality, as well as another health parameters. The skeletal muscle quantity and quality in obese individual may be determinant in how that the organism deals with theses problems. Thus, the objective of the present study was to verify the association between strength, muscle quantity and quality, functionality, vascular health and adiposity in obese subjects. Thirty four obese subjects, aged 20-60 years, sedentary, non-smokers and non-diabetic, volunteered to participate in the study. After a familiartization session, the knee extensors strength (isometric maximal volunatry contraction - IMVC; on repetition maximum - 1RM ; average power) and functional (6 minutes walk test - TC6M; sit to stand up test - 30SL; get up and go) tests were performed. The quadriceps femoris muscle thickness (EMQUA) and echo intensity (EIQUA) were evaluated by ultrasonography, as well as different adiposty parameters and vascular function. The pearson correlation coefficent were verified between all variables cited above and a P<0.05 were adopted. There was found a negative significant association between the EIQUA and all the strength tests performed, as well as all functional tests. The EMQUA presented significant positive association with all strength and functional tests. Additionally, the EIQUA presented a significant negative association with the visceral adipose tissue, as well as the thigh subcutaneous adipose tissue. Besides that, the abdominal subcutaneous adipose tissue was associated positively with the vascular function. The data presented here have shown a significant association between the muscle quantity and quality and the performance in functional and strength tests in obese subjects. In addition, important adiposity parameters correlated with the EIQUA and vascular function. Thus, intervention strategies (such as strength training), that are capable of modifying these parameters, should be prioritized when the objective is to enhance the quality of life in an obese person.

Objetivo: Verificar o efeito em longo prazo do tratamento da apneia do sono com CPAP na circunferência da cintura em pacientes com apneia do sono. Métodos: Foram incluídos indivíduos com apneia do sono de ambos os sexos, idade superior a 18 anos, com indicação de uso de CPAP que aderiram ou não ao tratamento. Todos foram submetidos à polissonografia de noite inteira pelo método convencional em laboratório do sono afiliado a universidade entre 01/01/2007 e 01/06/2012. O grupo com CPAP realizou pelo menos três polissonografias. O grupo controle foi composto por pacientes que repetiram a polissonografia após pelo menos seis meses, que relataram não receber qualquer tipo de tratamento e que mantinham o IAH na segunda polissonografia. Resultados: No grupo CPAP foram incluídos 77 pacientes e no grupo controle, 43 pacientes. O tempo de acompanhamento foi respectivamente de 2,5 e 2,3 anos. Foi observada uma redução significativa na circunferência abdominal no grupo CPAP, comparando com controles através do teste t de Student (P= 0,024). O modelo logístico binário para prever redução da circunferência abdominal após o período de acompanhamento foi significativo (P <0,001), utilizando-se como regressores: uso do CPAP, sexo, idade> 45 anos, IMC≥ 30 kg/m2 e IAH≥ 30. O R2 de Nagelkerke foi de 0,36, indicando que essas variáveis explicam 36% da variação da redução da circunferência abdominal. Conclusão: O uso de CPAP se associa à redução da circunferência abdominal, independentemente de sexo, idade e índice de apneia-hipopneia basais, bem como da diferença de índice de massa corporal. Este achado justifica pesquisas futura sobre o papel da apneia do sono no volume de gordura visceral. / Objective: Verify the long term effect of sleep apnea treatment with CPAP on waist circumference in patients with sleep apnea. Methods: Individuals of both genders, older than 18 years that adhered to CPAP use or not were included. All underwent a full-night polysomnography by the conventional method in a university-affiliated sleep laboratory between 01/01/2007 to 01/06/2012. The group using CPAP underwent at least three polysomnographies. The control group consisted of patients with moderate to severe OSA who repeated a polysomnography after at least six months. Only individuals who reported not receiving any treatment and in which the AHI continued in the same OSA categories at the second polysomnography were included. Results: The CPAP group included 77 and the control group, 43 patients. Follow up time was, respectively, 2.5 and 2.3 years. A significant reduction in waist circumference was observed in the CPAP group, comparing with controls by Student’s t test (P= 0.024). The binary logistic model to predict decreased waist circumference after follow up period was significant (P<0.001), using as regressors: CPAP use, gender, age>45 years, BMI≥30 Kg/m2, and AHI≥30. The Nagelkerke R Square was 0.36, indicating that these variable explain 36% of the variance of waist circumference reduction. Conclusion: Long-term CPAP therapy is associated with a reduction in waist circumference, regardless of sex, age and basal apnea-hypopnea as well as the difference in body mass index.

O atual quadro de obesidade instalado no mundo estimula o estudo em busca de seu tratamento. O fenofibrato, um agonista PPAR-&#945;, é usado atualmente para tratar a dislipidemia. No entanto, efeitos pleiotrópicos sobre a perda de massa corporal (MC) e redução nos depósitos de gordura necessitam de maiores estudos. O objetivo do trabalho foi examinar os efeitos do agonista PPAR-&#945; fenofibrato sobre o gasto energético, MC, metabolismo de carboidratos, perfil secretor de adipocinas, plasticidade e termogênese do tecido adiposo branco subcutâneo (TABs) em camundongos com obesidade induzida por dieta. Este experimento foi aprovado pelo Comitê de Ética para Experimentação Animal local sob o protocolo CEUA/032/2013. Camundongos machos C57BL/6 de 3 meses foram divididos em dois grupos: dieta padrão (SC, 10% lipídios) e dieta hiperlipídica (HF, 50% de lipídios), as quais foram administradas durante 10 semanas para induzir o sobrepeso. Em seguida, foi iniciado o tratamento com fenofibrato (100 mg/kg MC, adicionado à dieta), formando quatro grupos: SC, SC-F, HF, HF-F. O tratamento teve duração de cinco semanas, com o total de 15 semanas de experimento. A análise estatística utilizou teste t de student no pré-tratamento e one way ANOVA seguida pelo pós-teste de Holm-Sidak durante o tratamento. O two way ANOVA foi utilizado para testar possíveis interações entre dieta e tratamento. O nível de significância P<0,05 foi considerado estatisticamente significativo. O grupo HF apresentou sobrepeso, resistência à insulina, além de remodelamento do tecido adiposo branco subcutâneo (TABs). O fenofibrato atenuou significativamente estes parâmetros (P<0,05). Os grupos tratados apresentaram formação de células beges no TABs, confirmado através de maior expressão gênica do PPAR-&#945;, PPAR-&#946;, PGC1-&#945;, BMP8, UCP-1, PRDM16 e FNDC5/Irisina nos grupos tratados do que em suas contrapartes (P<0,05). O tratamento com fenofibrato também foi capaz de aumentar os niveis plasmáticos de FNDC5/Irisina em ambos os grupos tratados (P<0,005). Os grupos SC-F e HF-F apresentaram aumento do gasto energético, a produção de CO2 e consumo de O2 após o tratamento com fenofibrato (P<0,05). A ativação do PPAR-&#945; parece ser fundamental para provocar browning através da indução da irisina e da transcrição de UCP-1. O fenofibrato restaurou a MC, a sensibilidade à insulina e a morfometria do TABs. Relevantemente, o fenofibrato aumentou a expressão de genes tipicamente expressos no tecido adiposo marrom no TABs, evidenciando a plasticidade do TABs em células beges com capacidade termogênica, caracterizando o browning. / The current situation of obesity in the world encourages the study for its treatment. Fenofibrate, a PPAR-&#945; agonist, is currently used to treat dyslipidemia. However, its pleiotropic effects upon body mass loss and fat pads reduction remain to be unraveled. This study aimed to examine the effects of PPAR-&#945; agonist fenofibrate on energy expenditure, body mass, carbohydrate metabolism, secretory profile of adipokines, plasticity and thermogenesis in adipose tissue in diet-induced obese mice. Male C57BL/6 mice were fed a standard chow (SC; 10% lipids) diet or a high-fat (HF; 50% lipids) diet for 10 weeks. Afterwards, groups were subdivided into: SC, SC-F, HF and HF-F (n=10, each). Treatment with fenofibrate (100 mg/kg BM, mixed into the diet) was maintained for five weeks, totalizing fifteen weeks of experiment. All procedures were approved by the Animal Ethics Committee of UERJ (CEUA/032/2013). The differences among the groups were tested by one-way analysis of variance (ANOVA), followed by the Holm-Sidak post-hoc test. Two-way ANOVA was applied to test interactions between diet and treatment upon the evaluated outcomes. In all cases, P<0.05 was considered statistically significant. HF presented overweight, insulin resistance, besides adverse subcutaneous white adipose tissue (sWAT) remodeling. Fenofibrate attenuated significantly these parameters (P<0.05). Treated groups showed beige cells in sWAT, confirmed through higher gene expression of PPAR-&#945;, PPAR-&#946;, PGC1-&#945;, BMP8, UCP-1, PRDM16 and FNDC5/Irisin in treated groups than in their counterparts (P<0.05). The treatment with fenofibrate was also able to increase plasma levels of FNDC5/Irisin in both treated groups (P<0.005). SC-F and HF-F groups presented increase in energy expenditure, CO2 production and O2 consumption after treatment with fenofibrate (P<0.05). Activation of PPAR-&#945; seems to be pivotal to trigger browning through irisin induction and UCP-1 transcription. Fenofibrate restored body mass, insulin sensitivity and sWAT morphometry. Importantly, fenofibrate increased the expression of genes typical from brown adipose tissue (BAT) in sWAT, characterizing the plasticity of sWAT in beiges cells with thermogenic capacity, a phenomenon so-called browning.

Introdução: Ao ser usado o retalho de omento dissecado por videolaparoscopia no tratamento de deformidades da mama, foi constatado um significativo aumento do seu volume nos primeiros meses após a sua transposição, em todas as pacientes operadas, o que não é visto com essa magnitude em nenhum outro retalho adiposo. Métodos: Para se estudar o motivo desse aumento de volume, foram realizados estudos histológicos de amostras de omento coletadas no primeiro tempo cirúrgico, logo após sua transposição da cavidade abdominal para a região mamária e, no segundo tempo cirúrgico, durante a complementação de tratamento para a simetrização das mamas de oito pacientes. Foram documentadas as modificações nas medidas morfométricas dos adipócitos (perímetro, diâmetro e área), na densidade microvascular mediante o marcador endotelial CD31 e na expressão imunohistoquímica do fator de crescimento do endotélio vascular (VEGF). Resultados: O aumento do tamanho dos adipócitos e da densidade microvascular foi estatisticamente significativo (P≤0,012). O valor do VEGF foi menor na segunda amostra em relação com a primeira, redução esta que não atingiu significância considerável (P<0,093). Conclusão: Estes resultados sinalizam um aumento no volume celular que se mostrou consistente quando foram utilizados três diferentes processos de medida: perímetro, diâmetro e área dos adipócitos. Além disso, o aumento do número de vasos na segunda amostra sugere que tenha ocorrido neoangiogênese estimulada pelo aumento inicial dos valores do VEGF. Portanto o aumento do volume do retalho se deve a neovascularização e hipertrofia do adipócito. / Introduction: When laparoscopically harvested omentum flap was used to treat breast deformities, a significant volume increase, which had never been noticed in any other adipose flap, was observed in all the patients in the first months following its transposition. Methods: Histological studies of omentum samples were performed to study the reason for this increase. Samples were harvested at the first surgical time, right after the transposition of the omentum from the abdominal cavity to the breast region, and at the second surgical time, during treatment complementation for breast symmetrization of eight patients submitted to the transposition of the omentum flap. Modifications in the morphometric measurements of the adipocytes (perimeter, diameter, and area), in the microvascular density by the CD31 endothelial marker and in the imunohistochemic expression of VEGF were documented. Results: the increase in adipocyte size and microvascular density was statistically significant (P≤0.012). The value of VEGF was lower in the second sample, which was not significant (P<0.093). Conclusion: These results suggest an increase in cellular volume that was consistent when three different measurement procedures were used: adipocyte perimeter, diameter, and area. Moreover, the increase in the number of vessels in the second sample suggests neoangiogenesis stimulated by the initial increase in VEGF values obtained in the first sample. The flap increase was probably caused by adipocyte hypertrophy, resulting from the neoangiogenesis.