To gain insight in the relationship between innate immune system and metabolic disease, we aimed to investigate the effects of lactoferrin in obesity-related metabolic disturbances. Circulating lactoferrin concentration was significantly decreased in subjects with altered glucose tolerance (AGT) and associated negatively with obesity-related metabolic disturbances. The SNPs-induced aminoacidic changes in lactoferrin N-terminus region were associated with a low atherogenic lipid profile. Lactoferrin production in neutrophils decreased significatively in aging, chronic low-grade inflammation and type 2 diabetes. In vitro, lactoferrin increased insulin signaling pathway, even under insulin resistance conditions and displayed dual effects on adipogenesis (antiadipogenic in 3T3-L1 and adipogenic in human adipocytes). In conclusion, lactoferrin might play a potential protective role against insulin resistance and obesity related metabolic disturbances. / Per aprofundir en la relació entre el sistema immunològic innat i els trastorns metabólics, s’investiga l’efecte de la lactoferrina en els desordres metabòlics associats a l’obesitat. Els nivells circulants de lactoferrina es trobaven significativament disminuits en subjetes amb la tolerància a la glucosa alterada (AGT), i aquests es correlacionaven negativament amb trastorns metabòlics associats a obesitat i resistència a la insulina. Els canvis aminoacídics en la seva regió N-Terminal s’associaven a un perfil lipídic menys aterogènic. La producció de lactoferrina es troba reduïda en condicions d’envelliment, inflamació crònica i diabetes tipus 2. In vitro, la lactoferrina incrementava la via de senyalització de la insulina, inclús en condicions de resistència a la insulina i presentava efectes dual en la adipogenesis (antiadipogenic en 3T3-L1 i adipogenic en adipòcits humans). En conclusió, la lactoferrina podria tenir un potencial efecte protector enfront les enfermetats metabòliques associades a obesitat i resistència a la insulina.

O ψευδάργυρος -Zn ελέγχει τον μεταβολισμό των λιπιδίων και γλυκόζης μέσω Ζn-μεταγραφικών παραγόντων. Δίαιτες υψηλών λιπαρών οδηγούν στην ενδοκυτταρική συσσώρευση ελευθέρων ριζών, μειώνουν την μεταγραφική έκφραση των εκκαθαριστών τους και την ενεργότητα αντιοξειδωτικών ενζύμων και οδηγούν σε μεταβολικό σύνδρομο. Οι πρωτεϊνες του θερμικού shock (Heat shock proteins-HSP) παίζουν σημαντικό ρόλο στην αντίσταση στο κυτταρικό stress ως προσαρμογή ,μετά από έκθεση, σε διάφορα ερεθίσματα. ΣΚΟΠΟΣ : Μελέτη της επίδρασης του διατροφικού Ζn και των Hsp70,στην μεταβονομική των λιπιδίων αίματος και ήπατος ποντικών ΥΛΙΚΟ-ΜΕΘΟΔΟΙ :Ενήλικα αρσενικά ποντίκια: 1. Wild type (Wt) Hybrid (F1/F1) C57Bl/6 x CBA και 2. Transgenic (Tg) human HSP70 overexpressing mice, από ηλικίας ενός μηνός εντάχθηκαν στις παρακάτω διατροφές ,επί 10 εβδομάδες. Διατροφή Αριθμός Wt Αριθμός Tg Chow Diet (30 Zn) 6 10 High Fat Diet (3 Zn) 13 12 High Fat Diet (30 Zn) 9 8 High Fat Diet (300 Zn) 12 12 Σύνθεση των τριών διαιτών υψηλών λιπαρών -HFD: 3mg, 30mg, 300mg Zn /kg τροφής (mucedoola s.r.l Ιtaly-55% Cal από λιπαρά στοιχεία), Chow : δίαιτα ελέγχου Βιοχημικές αναλύσεις: Cholesterol ,Triglycerides ,HDL-cholesterol, Glucose ,Insulin Μετρήσεις μετάλλων και αντιοξειδωτικών παραγόντων: SOD (ερυθρά αιμοσφαίρια ) TAC (ορός αίματος) Zn , Cu (ερυθρά αιμοσφαίρια και ιστός ήπατος) Μεταβονομική ανάλυση και αξιολόγηση λιπιδίων :Εκχύλιση ορού αίματος και ηπατικού ιστού για λήψη Φάσματος 1H-NMR ΣΥΜΠΕΡΑΣΜΑΤΑ 1. Η HF δίαιτα αύξησε σημαντικά ,το τελικό βάρος και τον ρυθμό αύξησης βάρους ,τη χοληστερόλη -CL και την λιποπρωτεϊνη υψηλής πυκνότητας-ΗDL ,την ινσουλίνη –Ins, στα WT & Tg και μείωσε την ολική αντιοξειδωτική ικανότητα-TAC στο πλάσμα και την δραστηριότητα της σουπεροξείδιο-δισμουτάσης-SOD στα ερυθροκύταρα των WΤ και Tg 2. Ο επαρκής διατροφικός Zn (30mg/kgτροφής) φαίνεται να αποτελεί κρίσιμο παράγοντα διαμόρφωσης προστατευτικού ηπατολιπιδαιμικού προφίλ, ποντικών σε υπερλιπιδική δίαιτα. Η αύξηση ή μείωση του Zn σε HFDς φαίνεται να μειώνει την TAC του πλάσματος σε WΤ και Tg ενώ η δραστικότητα της SOD φαίνεται ανάλογη των επιπέδων του Zn Η ανεπάρκεια ή περίσσεια Zn αυξάνει τα αθηρογόνα SFA και μειώνει τα αντι-αθηρογόνα λιπίδια, PC, DU, LA DIAL ,UFA στις HDL, nonHDL και το ήπαρ, στα WΤHFD και στα ΤgHFD 3. Οι HSP70 : Τα διαγονιδιακά ζώα που φέρουν το γονίδιο hHsp70, φαίνεται ότι είτε σε έλλειψη είτε σε περίσσεια Ζn, που συνήθως συνοδεύoνται από μεταβολικό σύνδρομο, κατορθώνουν να διατηρούν καλλίτερους δείκτες λιπιδικού προφίλ σε σχέση με τα WT ζώα. Τα Τg εμφάνισαν σημαντικά χαμηλότερη CL ,TG , HDL σε σύγκριση με τα WT ενώ η HSP70 αύξησε σημαντικά την ενεργότητα της ολικής SOD στα ερυθρά αιμοσφαίρια. Η HSP70 μείωσε τα αθηρογόνα SFA και αύξησε τα αντιαθηρογόνα λιπίδια DIAL, DU, LA, UFA, SM στις HDL, nonHDL , και στο ήπαρ ποντικών που εκτέθηκαν σε HFD και σε όλες τις συγκεντρώσεις Zn. / Zinc –Zn controls lipid and glucose metabolism via Zn-transcription factors. High fat diets –HFDs lead to intracellular free radicals accumulation, decrease the transcriptional expression of their scavengers and anti-oxidative enzymes’ activity leading finally to metabolic syndrome. Heat shock proteins-HSPs play a significant role in cellular resistance response , as an adaptation mechanism, after exposure to various stimuli. SCOPE: To study the effects of nutritional Zn and HSP70s on the metabonomics of serum and liver lipids in mice MATERIALS-METHODS: Male mice: 1. Wild type (Wt) Hybrid (F1/F1) C57Bl/6 x CBA και 2. Transgenic (Tg) human HSP70 overexpressing mice, one month old, were subjected for 10 weeks to the following diets : Diet Number of Wt Number of Tg Chow Diet (30 Zn) 6 10 High Fat Diet (3 Zn) 13 12 High Fat Diet (30 Zn) 9 8 High Fat Diet (300 Zn) 12 12 Composition of the three HF Diets: 3mg, 30mg, 300mg Zn /kg τροφής (mucedoola s.r.l Ιtaly-55% Cal from greasy ingredients),Chow :control diet Biochemical analyses: Cholesterol ,Triglycerides ,HDL-cholesterol, Glucose ,Insulin Metals and antioxidative factors levels: SOD (red blood cells )TAC (blood serum) Zn , Cu (red blood cells and liver tissue) Lipids metabonomics : Blood serum and liver tissue extracts for 1H-NMR spectrum analysis and evaluation CONCLUSIONS 1. HFDiet significantly increased the rate of mice body weight gaining, as well as, cholesterol-CL, high density lipoproteins-HDL, insulin, in WT and Tg mice and decreased plasma total antioxidant capacity-TAC and red blood cell super oxide dismutase –SOD activity , in WT and Tg mice 2.Suficient nutritional Zn (30 mg/kg food) prevails as a crucial modulator of a protective hepato-lipidaemic profil of mice in high fat diet. Zinc deficiency or excessiveness , in HFDiets , decreases plasma TAC in WT and Tg mice, while SOD activity shows proportional to Zn levels. Zinc deficiency or excessiveness increases the atherogenic SFA and decreases the anti –atherogenic lipids : PC, DU, LA DIAL ,UFA, in HDL, nonHDL and liver, in WΤ-HFD and Τg-HFD mice 3. HSP70s : Transgenic mice over-expressing hHsp70 gene and exposed either to Zn deficiency or Zn excessiveness , both driving usually to metabolic syndrome , reveal significantly better lipid profile indicators, comparing to WT mice. Tg mice revealed significantly lower CL , TG , HDL levels compared to WT, while HSP70 in Τg mice significantly increased total SOD activity in red blood cells. HSP70 also decreased the atherogenic SFAs and increased the anti-atherogenic lipids DIAL, DU, LA, UFA, SM in HDL, nonHDL and in the liver of mice exposed to HFDiets and all Zn concentrations

<p>Conclusion of this study: These data suggest that 6 weeks of high-fat feeding induces hypertension but does not produce obesity, dyslipidemia and insulin resistance. However, this model may be useful in studying vascular reactivity in hypertension in the absence of insulin resistance.</p>

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A doença hepática gordurosa não alcoólica é uma desordem multifatorial causada principalmente por excesso nutricional e resistência à insulina, com prevalência estimada de 20-40% nos países ocidentais. A dieta hiperlipídica e/ou rica em sacarose pode influenciar no desenvolvimento da esteatose hepática associada à obesidade e a resistência à insulina. O fígado, por assumir papel central no controle metabólico, é um órgão alvo nos casos de excesso alimentar, ocasionando, principalmente, acúmulo de gotículas de gordura nos hepatócitos. Este trabalho teve como objetivo avaliar o início das alterações morfológicas e metabólicas no fígado e no tecido adiposo de camundongos suíços machos alimentados com dieta hiperlipídica e/ou rica em sacarose. Camundongos suíços machos aos três meses de idade foram divididos em quatro grupos nutricionais: dieta padrão (SC), dieta hiperlipídica (HF), dieta rica em sacarose (HSu) e dieta hiperlipídica rica em sacarose (HFHSu). Os animais receberam as respectivas dietas durante quatro semanas. A massa corporal, a ingestão alimentar e a tolerância oral à glicose foram avaliados. Ao sacrifício, o fígado e os depósitos de gordura corporal foram removidos e processados para análises histomorfométricas e moleculares. As amostras de sangue foram obtidas para análises bioquímicas plasmáticas. Os dados foram expressos como média e erro padrão da média e as diferenças foram testadas por one-way ANOVA com pós-teste de Holm-Sidak, e foi considerado o nível de significância de p<0,05. Os grupos HF e HFHSu apresentaram-se mais pesados quando comparados aos grupos SC e HSu. Os animais dos grupos HF, HSu e HFHSu apresentaram intolerância à glicose, esteatose hepática e aumento de triglicerídeos hepáticos quando comparados ao grupo SC (p<0,0005). Adicionalmente, houve elevação na expressão hepática das proteínas transportador de glicose 2 (GLUT-2), proteína de ligação ao elemento regulador do esterol 1-c (SREBP1-c), fosfoenolpiruvato carboxiquinase (PEPCK), glicose -6- fosfatase (G6PASE), substrato do receptor da insulinaI-1 (IRS-1) e proteína quinase B (AKt/ou PKB) e redução da expressão no fígado do receptor ativador de proliferação peroxissomal (PPAR-&#945;) nos grupos experimentais em comparação com o grupo SC (p<0,0005). A administração de dieta hiperlipídica e/ou rica em sacarose promoveu intolerância à glicose e danos hepáticos (hepatomegalia, esteatose, redução da beta-oxidação, aumento na lipogênese e na produção de glicose) em camundongos machos adultos. / The non-alcoholic fatty liver disease is a multifactorial disorder caused mainly by excess nutritional and insulin resistance, with an estimated prevalence of 20-40% in Western countries. The diet can to influence in the development of fatty liver associated with obesity and insulin resistance. The liver plays a central role in metabolic control, is a target organ, in case of excess of food, mainly causing accumulation of fat droplets in hepatocytes. This study aimed to evaluate the early morphological and metabolic changes in the liver and adipose tissue of male Swiss mice fed high-fat and/or high-sucrose diets. Twenty three-month-old male Swiss Webster mice were divided into 4 groups: standard chow (SC), high-fat diet (HF), high-sucrose diet (HSu) and high-fat-high-sucrose diet (HFHSu). Animals received the respective diets for 4 weeks; throughout the experiment, body mass, food intake and oral glucose tolerance were evaluated. After the mice were euthanized, the liver was removed and processed for histomorphometrical and molecular analysis. Blood samples were obtained for serum analysis. The data were tested by one-way ANOVA with a Holm-Sidak post-hoc test and were expressed as the mean standard error of the mean; the significance level was set at p < 0.05. The HF and HFHSu groups were heavier than the SC and HSu groups. Animals from the HF, HSu and HFHSu groups presented glucose intolerance, hepatomegaly, liver steatosis and augmented hepatic triglycerides when compared to the SC group (p<0.0005). Additionally, there was an elevation in glucose transporter 2 (GLUT-2), sterol regulatory element binding protein-1c (SREBP-1c), phosphoenolpyruvate carboxykinase (PEPCK), glucose 6 phosphatase (G6PASE), insulin receptor substrate 1 (IRS-1), protein kinase B (AKT/ or PKB) protein expression and a reduction in peroxisome proliferator-activated receptor alpha (PPAR-alpha) expression in liver from the experimental groups compared to those of the SC group (p<0.0005). Administration of high-fat and/or high-sucrose diets promoted glucose intolerance and liver damage (hepatomegaly, steatosis, reduced beta-oxidation, increased lipogenesis and glucose production) in adult male mice.

L’hypothalamus est une aire cérébrale clé pour le contrôle de la prise alimentaire et des dépenses énergétiques ; en intégrant des signaux périphériques (hormones, nutriments). Une inflammation dans l’hypothalamus pourrait perturber le fonctionnement de ce dernier, dérégulant l’homéostasie énergétique et induire une perte de poids ou l’obésité. Nous avons cherché à identifier les relais moléculaires entre l’inflammation et les systèmes neuropeptidergiques hypothalamiques régulant l’homéostasie énergétique, en nous concentrant sur les chimiokines. D’une part, nous avons montré que le récepteur CCR2 participe à la perte de poids liée à une inflammation aigue induite chez la souris par l’injection centrale de lipopolysaccharide bactérien, possiblement en induisant l’inhibition de l’activité des neurones hypothalamiques à MCH, peptide aux effets orexigènes. D’autre part, nous avons étudié les liens entre inflammation hypothalamique, gain de poids et/ou la consommation de régimes hyperlipidiques pouvant induire à terme une obésité. Nous avons trouvé, chez la souris, que 1) la chimiokine CCL5 favoriserait la prise de poids, possiblement en activant les neurones hypothalamiques à MCH ; 2) la nature des lipides d’un régime hyperlipidique impacterait la cinétique de développement de l’obésité, avec des changements du profil inflammatoire et 3) la consommation excessive de lipides induirait une gliose très précoce dans l’hypothalamus. L’ensemble de nos résultats souligne l’intérêt de cibler l’inflammation hypothalamique dans ces pathologies et identifient les chimiokines comme cibles thérapeutiques potentielles dans le traitement des dérégulations de la balance énergétique. / The hypothalamus is a key brain region in the regulation of energy homeostasis, in particular by controlling food intake and energy storage and expenditure by integration of peripheral humoral and nutrient-related signals. Hypothalamic inflammation could alter hypothalamic function, thus deregulate energy homeostasis and induce weight-loss or obesity. We sought to identify mediators that could act as intermediaries between inflammation and neuropeptidergic systems of the hypothalamus that are involved in the regulation of energy homeostasis, focusing on chemokines. First, we studied the effect of a central injection of bacterial lipopolysaccharide, mimicking a acute and strong inflammation state in mice. We identified the receptor CCR2 as a central actor in the weight-loss induced by this treatment, possibly by direct inhibitory effects on hypothalamic neurons expressing MCH, a peptide known to have orexigenic and energy conservative effects. Second, we studied links between hypothalamic inflammation, weight-gain and/or high-fat diets consumption that can induce, eventually, obesity. We found in mice that: 1) the chemokine CCL5 would promote weight-gain, possibly by enhancing the activity of hypothalamic MCH neurons; 2) altering the lipid composition of a high-fat diet changes the kinetics of the development of diet-induced obesity, together with changes in the inflammatory profile and 3) an excessive dietary lipid intake can induce very early gliosis in the hypothalamus. Taken together, our results underline the interest of reducing hypothalamic inflammation to fight feeding behavior deregulations and identify chemokines as putative therapeutic targets.

Well functioning circadian system is crucial component of healthy organism and its disruption can result in impairment of metabolic functions with consequential development of obesity and type 2 diabetes mellitus. Obesity is in general caused by enhanced migration of pro- inflammatory polarized macrophages (M1) into adipose tissue. We have shown, that interaction of this type of macrophages with adipose tissue had significant effect on rhythmic expression of clock genes in adipocytes. We further investigated effect of high fat diet and diet enriched by omega-3 fatty acids on circadian oscillations in WAT and differently polarized macrophages. This diet affected oscillations in adipose tissue and in M0 and M2 polarized macrophages. These results support previous findings of effect of omega-3 fatty acids on metabolism and suggest their effect on circadian system as well. Key words: circadian rhythms, adipose tissue, macrophages, omega-3 fatty acids, high fat diet

Objetivo: Sabe-se que trabalhadores noturnos tem preferência por lanches com maior concentração de gordura saturada. Trabalhadores de turno, particularmente trabalhadores noturnos, apresentam mais frequentemente hipertrigliceridemia e hiperglicemia, bem como menores níveis de HDL-colesterol quando comparados a trabalhadores diurnos, devido a alterações circadianas e estilo de vida, sugerindo uma predisposição para o desenvolvimento de doenças cardiovasculares. Estas alterações são conhecidas como Síndrome Metabólica (SM). Portanto, para entender as conseqüências de uma dieta hiperlipídica é importante a padronização de dietas para modelos animais que mimetizem a alimentação do trabalhador de turno. Materiais e Método: estudo experimental com 20 ratos Wistar dos quais 10 eram controle (CG) e 10 submetidos à dieta hiperlipídica (HFD). Utilizaram-se três dos cinco critérios do NCEP-ATP III para diagnóstico de SM - glicose, triglicerídeos (TG) e HDL-col. A quantidade de tecido adiposo visceral (TAV) foi avaliada bem como o peso do fígado e das glândulas adrenais. O peso ponderal foi avaliado semanalmente e o a ingestão alimentar e hídrica diariamente. Foi utilizado o t-test de Student’s para amostras independentes. Resultados: não houve diferença significante entre os grupos para glicose, HDL-col e TG na medida basal. Após 15 semanas de intervenção, grupo HFD mostrou um aumento dos níveis de TG (p=0,01) e glicose (p=0,01) e diminuição de HDL-col (p=0,009) quando comparados com CG. Grupo HFD apresentou maior TAV (p=0,005) e peso do fígado (p=0,01). CG mostrou um aumento de ingestão alimentar e hídrica (p<0,001 e p<0,001 respectivamente) enquanto que o consumo energético foi maior no grupo HFD (p<0,001). Não foi encontrada diferença no peso das glândulas adrenais (p=0,07) e peso ponderal (p=0,63). Conclusão: os animais submetidos à dieta hiperlipídica apresentaram alterações metabólicas apesar da manutenção do peso corporal. Não foi encontrada correlação entre peso corporal e quantidade de TAV, sugerindo que o peso corporal não é preditor para quantidade de gordura corporal e que a composição da dieta influi diretamente nos marcadores de SM. / Background and Aim: Shift workers, particularly night workers, more frequently present metabolic changes when compared to day workers suggesting a predisposition for cardiovascular disease. These changes are known as Metabolic Syndrome (MS). Therefore, to increase understanding of the consequences of a high-fat diet it is important to standardize a diet for experimental animals that mimics the shift workers’ diet and its effects. Methods and Results: experimental study with 20 Wistar rats of which 10 were control group (CG) and 10 high-fat diet group (HFD). Three of five criteria for MS diagnosis from NCEP-ATP III were assessed. The amount of visceral adipose tissue was determined (VAT). Body weight was assessed weekly and food and water intake were measured daily. Student’s t-test for independent samples was used. The groups were similar at baseline. After fifteen weeks of intervention, HFD group showed an increase in serum TG (p=0.01) and glucose (p=0.01) levels and a decrease in HDL (p=0.009) compared to CG. HFD showed increased VAT (p=0.005) and liver weight (p=0.01). Food intake and water intake were higher in CG (p<0.001 and p<0.001 respectively) while energy intake was increased in HFD (p<0.001). No difference was found in adrenal glands weight (p=0.07) and body weight (p=0.63). Conclusion: Animals submitted to HFD present significant metabolic alterations in spite of the maintenance of body weight. Body weight is not a predictive factor for the amount of VAT and that the quality of diet composition direct influences MS markers.

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2012-08-29T20:39:47Z No. of bitstreams: 1 Siane Campos. Avaliação dos efeitos de terapias com celulas de medula óssea modelo experimental de diabetes mellitus tipo 2.pdf: 7027812 bytes, checksum: 4b12aa1315741fb327aacac8f55889a7 (MD5) / Made available in DSpace on 2012-08-29T20:39:47Z (GMT). No. of bitstreams: 1 Siane Campos. Avaliação dos efeitos de terapias com celulas de medula óssea modelo experimental de diabetes mellitus tipo 2.pdf: 7027812 bytes, checksum: 4b12aa1315741fb327aacac8f55889a7 (MD5) Previous issue date: 2010 / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, Bahia, Brasil / O diabetes mellitus tipo 2 (DM2) é uma disfunção metabólica que afeta milhões de pessoas em números crescentes em todo o mundo. É caracterizado pela resistência dos tecidosalvo à insulina e/ou defeitos na sua secreção, acarretando uma hiperglicemia crônica, que pode gerar danos no sistema cardiovascular, nervoso, olhos, rins e fígado e representam um ônus para os sistemas de saúde. Doença de etiologia múltipla, o DM2 resulta da interação entre predisposição genética e fatores ambientais, destacando-se a obesidade. O tratamento do DM2 geralmente envolve mudanças de hábito e drogas anti-hiperglicemiantes ou hipoglicemiantes que podem acarretar efeitos colaterais. As recentes descobertas sobre a plasticidade e o potencial terapêutico das células-tronco de medula óssea indicam uma possível aplicação destas no tratamento do DM2 e suas complicações. Para investigar esse potencial, foi estabelecido um modelo de diabetes em camundongos C57Bl/6 através da administração de dieta hipergordurosa. Após o período de indução, os animais apresentavam obesidade, hiperglicemia, intolerância à glicose, proteinúria e esteato-hepatite não-alcoólica. Camundongos C57Bl/6 fêmeas não desenvolvem obesidade, hiperglicemia e DM2 quando submetidas à mesma dieta que os machos. Apenas os machos foram então tratados com células mononucleares de medula óssea e acompanhados durante seis meses. A terapia com células mononucleares de medula óssea não reduz o peso corpóreo dos animais obesos e diabéticos. Três e seis meses após a terapia, não foi observada redução da glicemia de jejum dos animais.Três meses após a terapia, observou-se redução da intolerância a glicose nos animais alimentados com dieta high-fat.Houve uma redução da fibrose perissinusoidal no fígado após 3 meses de terapia e esta diferença se manteve até 6 meses após a terapia. / Type 2 diabetes mellitus (T2DM) is a metabolic disorder that affects millions of people and grows worldwide. It is characterized by insulin resistance in peripheral tissues and/or impaired insulin secretion, leading to chronic hyperglycemia associated with long-term consequences that include damage and dysfunction of the cardiovascular system, eyes, kidneys and nerves. T2DM is a multifactorial disease determined by genetic and environmental factors, especially obesity. The usual treatment involves antihyperglycemic and hypoglycemic drugs that can provoke undesirable side effects. Recent findings on hematopoietic stem cell plasticity and therapeutic potential suggest their use as an alternative treatment for T2DM and its consequences. In order to investigate this potential, a model of diabetes was induced in C57Bl/6 mice through administration of a high-fat diet. Animals developed obesity, hyperglycemia, glucose intolerance, proteinuria and nonalcoholic steato-hepatitis. Female C57Bl/6 mice do not developed obesity, hyperglycemia and T2DM when submitted the male’s diet. After the induction period, only the male mice were treated with bone marrow mononuclear cells and observed during 6 months. Cell mononuclear from bone marrow therapy do not reduced body weight from obesity and diabetes animals. Three and six months after the therapy, we do not observed reduction from glycemia. Three months after the therapy, observed reduction glucose intolerance in mice high-fat fed. Reduction in fibrosis perisinusoidal liver after thee months from therapy and this difference still until six months after therapy.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A obesidade e suas complicações metabólicas afetam o sistema endócrino e vários órgãos, tais como os testículos. Portanto, o objetivo deste estudo foi avaliar os efeitos da ingestão de diferentes dietas hiperlipídicas (rica em ácidos graxos saturados e/ou poliinsaturados) na massa corporal, no metabolismo de carboidratos e na morfologia testicular em ratos aos sete meses de idade. 39 ratos machos Wistar (três meses de idade) foram divididos em 4 grupos: SC (standard chow; n = 9), HF-S (dieta hiperlipídica rica em ácidos graxos saturados; n = 10), HF-P (dieta hiperlipídica rica em ácidos graxos poliinsaturados; n = 10), HF-SP (dieta hiperlipídica rica em ácidos graxos saturados e poliinsaturados; n = 10). A massa corporal foi monitorada semanalmente, até o final do experimento. Ao sacrifício (sete meses de idade), amostras de sangue foram coletadas e os testículos foram dissecados, pesados e processados para análises histomorfométrica, imunohistoquímica e bioquímica. Os depósitos de gordura genital foram dissecados e pesados. Os dados foram analisados por ANOVA e pós-teste de Bonferroni, considerando p < 0,05. As dietas hiperlipídicas promoveram aumento na massa corporal dos animais quando comparado ao grupo SC (p < 0,0001). Corroborando com esse resultado, os depósitos de gordura genital dos grupos hiperlipídicos (HF-S, HF-P e HF-SP) apresentaram aumento de 67%, 91% e 90% (p = 0,0004) em relação ao grupo SC, respectivamente. Quanto aos parâmetros séricos, os animais dos grupos HF-S e HF-SP apresentaram hiperglicemia (p = 0,0060), hiperinsulinemia (p = 0,0030), hipercolesterolemia (p = 0,0021). Todos os grupos hiperlipídicos apresentaram hiperleptinemia (p = 0,0019). Os níveis de triglicerídeos e testosterona não diferiram entre os grupos. Em relação ao testículo, os grupos SC, HF-P e HF-SP apresentaram maior altura do epitélio seminífero quando comparado ao grupo HF-S (p = 0,0003). No que diz respeito ao diâmetro dos túbulos seminíferos, verificou-se uma diminuição no grupo HF-SP, em comparação ao grupo SC (p = 0,0010). A proliferação celular foi reduzida no grupo HF-S comparado ao grupo SC (p = 0,0450). Não foram observadas diferenças na massa testicular e na concentração de colágeno. Diante do exposto, a administração de dieta HF, independentemente da qualidade do lipídio, promoveu o sobrepeso em ratos adultos. No entanto, a dieta rica em ácidos graxos saturados (banha de porco) promoveu alterações no metabolismo dos carboidratos e na morfologia testicular, com redução no diâmetro dos túbulos seminíferos, na altura do epitélio seminífero e na proliferação das células da linhagem espermatogênica. Estas alterações estão possivelmente relacionadas à distúrbios na espermatogênese. / Obesity and its metabolic complications affects the endocrine system and multiple organs such as the testes. This study aimed to evaluate the effects of different high-fat diets (rich in saturated and / or polyunsaturated fatty acids) on body mass, carbohydrate metabolism and testicular morphology in rats at seven months old. 39 male Wistar rats (three months old) were divided into four groups: SC (standard chow, n = 9), HF-S (high fat diet rich in saturated fatty acids, n = 10), HF-P (high fat diet rich in polyunsaturated fatty acids, n = 10), HF-SP (high fat diet rich in saturated and polyunsaturated fatty acids, n = 10). Body mass was monitored weekly until the end of the experiment. At the sacrifice (seven months old), blood samples were collected and the testes were dissected, weighed and processed for histomorphometrical, immunohistochemical and biochemical analysis. Genital fat deposits were dissected and weighed. Data were analyzed by one-way ANOVA and Bonferroni post hoc test, considering p < 0.05. Different high-fat diets promoted an increased in body mass compared with the SC group (p < 0.0001). Accordingly, the genital fat deposits were higher in the high-fat groups (HF-S, HF-P, HF-SP) than in the SC group, showing an increase of 67%, 91% and 90%, respectively (p = 0.0004). Regarding serum parameters, the animals in the HF-S and HF-SP groups presented hyperglycemia (p = 0.0060), hyperinsulinemia (p = 0.0030), hypercholesterolemia (p = 0.0021). All of the hyperlipidemic groups showed hyperleptinemia (p = 0.0019). Serum triglyceride and serum testosterone levels did not differ among the groups. Concerning the testis, the SC, HF-P and HF-SP groups showed an increase on seminiferous epithelium height compared with the HF-S group (p = 0.0003). As the seminiferous tubule diameter, there was a decrease in the HF-SP group in comparison with the SC group (p = 0.0010). Cell proliferation was reduced in HF-S group compared with the SC group (p = 0.0450). Among the groups, no difference was observed in the testicular mass and in collagen level. In conclusion, the high fat diet administration, independent of the lipid quality, promotes overweight. Diet rich in saturated fatty acids (lard) alters the carbohydrate metabolism and the testicular morphology with reductions of seminiferous epithelium height, seminiferous tubule diameter and cell proliferation which could be related to a disturbance of spermatogenesis.