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The objective was to evaluate the insulin-leptin interactions in grazing mares and their impact on aspects of reproductive function using a series of four studies. Fourteen mares were first examined, 10 grazing and 4 confined to stalls in four 22-h studies in April, August, October (2005) and January (2006). There was a positive relationship between insulin and leptin concentrations (r = 0.50; P < 0.001). The second study used 24 mares maintained at pasture and fed supplements rich in either FF, or SS, or pasture forage. Nonstructural carbohydrate (NSC) content of forage was correlated to insulin concentration (r = 0.55; P < 0.01). Insulin was associated with leptin (r = 0.55; P < 0.001) and progesterone (r = 0.48; P < 0.001). In the third study nine mares adapted to FF, SS or forage only underwent two FSIGT tests; once during the luteal phase and again during the follicular phase of the estrous cycle. Minimal model analysis was used to describe insulin sensitivity (SI), glucose effectiveness (Sg), acute insulin response to glucose (AIRg) and the disposition index (DI). SI was lower (P < 0.001) in the luteal phase (3.1 ± 0.6) compared to the follicular phase (5.0 ± 0.6). In the fourth study 15 mares had their follicular fluid collected during the luteal and follicular phase of the estrous cycle. Insulin concentration (ln (x+1)) was 52% higher (P < 0.01) in large (> 25 mm) follicles (1.4 ± 0.1 mIU/L) than either medium (16 to 25 mm) or small (le; 15 mm) follicles (0.9 ± 0.1; 0.9 ± 0.1 mIU/L, respectively) irrespective of estrous cycle phase. A correlation was observed between follicular fluid (FFL) leptin and plasma leptin (r = 0.30; P < 0.001). A similar relationship was observed between FFL insulin and plasma insulin (r = 0.25; P < 0.001). Plasma insulin and leptin were positively associated (r = 0.45, P < 0.0001), along with FFL insulin and FFL leptin (r = 0.46, P < 0.0001). Both leptin and insulin were affected by season and this observation contradicts the use of single sample analysis for determining detrimental concentrations of these hormones. / Ph. D.

Background and Purpose: Little is known about influences of obstructive sleep apnea syndrome (OSAS) on dietary intake and body composition. The purpose of this study was to evaluate dietary status, body fat distribution and leptin in overweight young men with and without OSAS in comparison to published values for normal weight counterparts. Methods: Groups were comprised of 24 sedentary overweight young men with and without OSAS, who had a body mass index (BMI) greater than 25 kg/m². Serum leptin concentration was measured in the 24 subjects using radioimmunoassay, while OSAS assessment was done using nighttime home somnography. Analysis of 4-day diet recalls was performed using Nutritionist Pro (First DataBank, Inc., San Bruno, CA). A Healthy Eating Index (HEI) score was calculated for the 24 overweight subjects. Results: There were no differences between the two overweight groups for total fat mass, central abdominal fat, BMI, waist circumference, leptin, or the HEI. The HEI was not predictive of overall OSAS severity; however, BMI was moderately related to OSAS severity (r = 0.39; p=0.05). The normal weight group did have a 50% higher report of carbohydrate intake, and consumed on average, 500 more kilocalories per day. The normal weight group consumed 50% less sodium, and 50% more Vitamin's C and E including a 13% increase in the HEI. Conclusions: Regulation of eating behavior and related influences on diet composition may be affected by a number of neurohormonal disturbances associated with OSAS and/or obesity, itself. Further research is needed to quantify these possible differences on dietary status and the underlying mechanism involved. / Master of Science

Hintergrund: Leptin ist ein unabhängiger kardiovaskulärer Risikofaktor und scheint prothrombotische Effekte zu besitzten. Adiponectin hingegen scheint vor Thrombosen zu schützen. Wir untersuchten deswegen die Bedeutung dieser beiden Adipozytokine bei Patienten mit einer akuten Lungenembolie. Durchführung: Im Rahmen einer prospektiven Fall-Kontroll-Studie schlossen wir zwischen 2003 und 2006 97 Patienten mit gesichterter Lungenembolie und 40 Patienten mit dem Ausschluß einer Lungenembolie ein. Die Lungenembolie-Patienten wurden bezüglich eines komplizierten Verlaufs innerhalb der ersten 30 Tage nach dem Ereignis (Tod, Katecholaminebedarf, Reanimation, Intubation, Hypotonie) sowie bezüglich des Langzeit-Überlebens beobachtet. Ergebnisse: Bei Patienten mit Lungenembolie ist ein höherer Leptinspiegel ein prognostischer Parameter für eine niedrigere 30-Tages-Komplikationsrate und ein besseres Langzeit-Überleben. Patienten mit einer Lungenembolie weisen signifikant höhere Adiponectinwerte als Patienten ohne Lungenembolie auf. Eine prognostische Bedeutung hat Adiponectin bei Patienten mit einer Lungenembolie nicht. Schlußfolgerung: Niedrige Leptinspiegel sind bei Patienten mit einer akuten Lungenembolie ein unabhängiger prognostischer Parameter für einen komplizierten 30-Tages-Verlauf und eine erhöhte Mortalität im Langzeit-Verlauf. Lungenembolie-Patienten weisen eine Hyperoadiponectinämie auf, dies könnten Ausdruck einer kardialen Sekretion und Wirkung des Asiponectins infolge der Lungenembolie sein.

Le traitement de l’obésité est devenu un problème majeur de santé publique aussi bien dans les pays industrialisés que dans les pays en voie de développement. La leptine est une hormone clé dans le contrôle de l’homéostasie énergétique et glucidique en agissant au niveau du noyau arqué de l’hypothalamus (ARC). La résistance à la leptine au niveau de ce noyau hypothalamique contribue au développement de l’obésité. Par conséquent, prévenir son installation et lever cette résistance constitue un enjeu thérapeutique majeur. Notre laboratoire à récemment mis en évidence que la protéine Endospanine 1 est un régulateur négatif des fonctions du récepteur de la leptine (OB-R). En effet, cette protéine, exprimée à partir du même gène qu’OB-R, est capable d’interagir avec ce récepteur et de le retenir dans le compartiment intracellulaire. L’extinction d’Endospanine 1 spécifiquement au niveau de l’ARC prévient l’installation d’une obésité induite par un régime gras. Ces données démontrent donc, in vivo, l’importance de cette protéine dans la régulation des fonctions d’OB-R. Suite a ces résultats prometteurs, l’objectif premier de ma thèse a été d’approfondir nos connaissances sur le rôle joué, in vitro et in vivo, par Endospanine 1, ainsi que par son homologue Endospanine 2, dans la régulation des fonctions d’OB-R. Le second objectif de ce travail de thèse a été d’identifier de nouveaux composés capables de sensibiliser la réponse à la leptine chez les individus obèses. Ce travail a permis de montré que des souris rendues obèses par un régime gras présentaient une surexpression d’Endospanine 1 dans l’ARC suggérant ainsi une potentielle implication de cette protéine dans le développement de la résistance à la leptine. D’autre part, nous avons démontré que l’extinction d’Endospanine 1, dans l’ARC, permet de prévenir l’installation d’une obésité et de la corriger chez des souris obèses et conduit à une altération de la sécrétion d’insuline par le pancréas. Cet effet double sur le poids corporel et sur la glycémie pourrait être expliqué par l’effet différentiel de l’extinction d’Endospanine 1 sur l’activation des voies STAT3 et PI3K/AKT. En effet, en absence d’Endospanine 1 la voie STAT3 est suractivée tandis que la voie PI3K est inhibée. De façon surprenante, l’extinction d’Endospanine 2, second membre de la famille des Endospanines, inhibe de façon drastique l’activation de la voie STAT3 suggérant que ces protéines pourraient jouer des rôles différents dans la régulation des fonctions d’OB-R. Ce travail a également permis de décrire, pour la première fois, les conséquences d’une déficience en Endospanine 1 chez l’Homme. Nos données suggèrent qu’Endospanine 1 ne régule pas les fonctions d’autres protéines, définissant ainsi Endospanine 1 comme une cible thérapeutique hautement spécifique dans la correction de la signalisation leptine.La dernière partie de cette étude a consisté en l’identification de nouveaux composés capables d’activer OB-R ou d’augmenter son expression de surface. Deux tests de criblages ont permis d’identifier de telles molécules. Après validation et caractérisation, de tels composés pourraient être utilisés comme outils thérapeutique afin de restaurer la sensibilité à la leptine perdue chez les individus obèses. / Obesity is one of the greatest current public health challenges, not only in industrialized countries but also in developing countries. The hypothalamic arcuate nucleus (ARC) is a major integration centre for energy and glucose homeostasis that responds to peripheral hormones such as leptin. Resistance to leptin in the ARC is an important component of obesity development and its prevention or reversal represents a major therapeutic goal. Our laboratory recently described endospanin 1 as a negative regulator of the leptin receptor (OB-R) that by interacting with OB-R retains the receptor inside the cell. Interestingly, both proteins are expressed from the same promoter. Silencing of endospanin 1 in the ARC prevented the development of diet-induced obesity demonstrating the importance of this protein on OB-R in vivo function.Based on these encouraging findings the first aim of this thesis was to extend our understanding of the in vitro and in vivo role of endospanin 1 and its homologue, endospanin 2, on OB-R function. The second aim consisted in the identification of chemical compounds able to sensitize the leptin response in obese patients. We show here that endospanin 1 is up-regulated in the ARC of obese mice suggesting a potential contribution of this protein to the development of leptin resistance. Its silencing in the ARC of naïve and obese mice reverses obesity development and impairs pancreatic insulin secretion. This dual effect correlates with the differential effect of endospanin 1 on OB-R signaling, inhibition of the STAT3 pathway and activation of the AKT pathway. Intriguingly, endospanin 2, the second member of the endospanin family, promotes efficient STAT3 activation suggesting differential roles of both endospanins on OB-R function.We characterized an obese patient carrying a homozygous deletion in the chromosomal 1p31.3 region coding for endospanin 1. This is the first report defining the consequences of endospanin 1-deficiency in humans. Our data suggest that endospanin 1 has no major OB-R-independent functions thus defining endospanin 1 as an attractive and highly specific therapeutic target for the improvement of impaired leptin signaling.In the last part of the thesis two screening assays were developed to identify compounds that either activate OB-R or promote its cell surface expression. Primary screens were successfully performed for both assays and positive hits identified. Validated hits might be useful to resensitize the impaired leptin response in obese patients.

Infertility is one of the major problems of obesity. Studies have shown that administration of leptin reversed obesity-induced infertility in rats and mice. Coenzyme Q10 (CoQ10) is an antioxidant and also supplies the energy needed for ovulation and embryo development. We hypothesized that leptin when combined with CoQ10 could greatly improve obesity-induced infertility. The results showed a significant decrease in food intake, body weight, and the regular estrous cycle was restored after treatment with leptin+CoQ10. There was a significant increase (p10 significantly (p10 can improve fertility in obese infertile female rats. This study could provide a novel therapeutic strategy for the treatment of infertility and formulation of new drugs for the treatment of obesity-induced infertility in females.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 6 uppsatser. På omslag felaktigt: Fat mass, adipokines and clinical complications of chronic kidney disease.

Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro / O objetivo deste estudo foi avaliar o efeito da administração de leptina no lobo ventral da próstata de ratos adultos. Vinte ratos Wistar machos e adultos foram divididos em 2 grupos: L - animais foram injetados com 50 μL diária de leptina (8 μg / 100 g PC, subcutânea) durante quatro dias e C - animais receberam o mesmo volume de solução salina. Perfil lipídico e níveis séricos de testosterona foram avaliados. O lobo ventral da próstata foi processado para análise histomorfométrica. Expressão dos genes da aromatase, receptor de andrógeno, receptores de estrógeno (α e β) e as isoformas dos receptores de leptina longa (Ob-Rb) e curta (Ob-Ra) foram avaliados por PCR em tempo real. Proliferação celular foi avaliada por imuno-histoquímica com PCNA. Os dados foram expressos como média  erro padrão e analisados pelo teste t de Student. Níveis séricos de colesterol aumentaram (C = 39,7 4,2; L = 55,2 4,2, mg / dL, P ≤ 0,02) e de testosterona (C = 1,6 0,43; L = 0,6 0,15, ng / dL, P ≤ 0,03) diminuíram no grupo L. A análise histomorfométrica mostrou uma redução na densidade de células (C = 8868 242; L = 8.211 210, mm2; P ≤ 0,04), na área total (C = 0,24 0,026; L = 0,10 0,009, mm2; P ≤ 0,001) e na área interna dos ácinos (C = 0,16 0,009; L = 0,08 0,006, mm2; P ≤ 0,0002). Por outro lado, houve um aumento na altura do epitélio (C = 17,3 0,3; L = 22,8 0,2 m, P ≤ 0,0001) e no número de ácinos (C = 7,0 0,2; L = 8,7 0,1, mm2; P ≤ 0,0002). As análises histomorfométrica juntamente com os resultados imuno-histoquímicos para PCNA sugerem que a leptina aumenta a proliferação celular. Em relação à expressão gênica, o tratamento de leptina aumentou a expressão de todos os genes, mas ER-α, em mais de 200 vezes em comparação com a expressão no grupo C. Em conclusão, neste trabalho mostramos que a leptina tem um efeito direto sobre a próstata de ratos adultos levando a um aumento na proliferação celular e na expressão gênica da aromatase, receptor de androgênio, nas isoformas dos receptores de leptina e receptores de estrogênios alfa e beta que são importantes para a fisiologia normal do tecido prostático / The aim of this study was to evaluate the effect of leptin administration on the ventral prostate lobe of adult rat. Twenty adult male rats were divided into 2 groups: L - animals were daily injected with 50 μL of leptin (8 g / 100 g BW, subcutaneous) for four days and C -animals received the same volume of saline solution. Lipid profile and testosterone serum levels were evaluated. The prostate ventral lobe was processed for histomorphometric analysis. Gene expression of aromatase, androgen receptor, leptin and estrogen receptors isoforms was evaluated by real-time PCR. Cell proliferation was evaluated by PCNA immunohistochemistry. Data were expressed as mean  standard error and analyzed by students t-test. Serum levels of cholesterol (C = 39.7 4.2; L = 55.2 4.2, mg / dL; P ≤ 0.02) increased and testosterone (C = 1.6 0.43; L = 0.6 0.15, ng / dL; P ≤ 0.03) decreased in L group. The histomorphometric analysis showed a reduction in cell density (C = 8868 242; L = 8211 210, mm2; P ≤ 0.04), in total (C = 0.24 0.026; L = 0.10 0.009, mm2; P ≤ 0.001) and in the internal acini areas (C = 0.16 0.009; L = 0.08 0.006, mm2; P ≤ 0.0002). On the other hand, there was an increase in the epithelial height (C = 17.3 0.3; L = 22.8 0.2, m; P ≤ 0.0001) and in the number of acini (C = 7.0 0.2; L = 8.7 0.1, mm2; P ≤ 0.0002). The histomorphometric analyses together with PCNA immunohistochemistry results suggest that leptin increases cell proliferation. In relation to the gene expression, leptin treatment increased the expression of all genes, but ER-α, in more than 200 times compared to the expression in C group. In conclusion, in this paper we showed that leptin has a direct effect on the prostate gland of adult rats leading to an increase in proliferation and in the gene expression of aromatase, androgen, leptin and estrogen receptors isoforms that are important for the physiology of the prostate gland.