Obesity is a health problem that is increasing worldwide and has high socioeconomic impact. In Sweden, obesity costs the society 70 billion SEK every year. For the year 2030, the Institute for Health and Medical Care Economics predicts that obesity can cost the society up to 17 billion SEK more than in 2018. In Sweden, 52% of the citizens 16-84 years of age are either overweight or obese.  The main factor behind obesity is still unidentified. What is known, and almost self-evident, is that weight gain occurs when energy consumption is lower than energy intake. The calorie intake during a day should be 1600-3000 calories and physical activity is important. For weight loss, the focus is mostly on calorie intake, but it is also important to consider the metabolic homeostasis which is regulated by hormones. Obesity can occur when there is a disturbance in the homeostatic mechanisms. One of the most important regulatory hormones is glucagon-like-peptide-1 (GLP-1) which stimulates satiety. Liraglutide and semaglutide are both GLP-1-analogues and are used in the treatment of type 2 diabetes. Liraglutide is also indicated in obesity and semaglutide as an anti-obesity drug has just undergone a phase 3 study. The mechanism of action of GLP-1-analogues in obesity is to stimulate a feeling of satiety, which leads to a lower energy intake and thus weight loss.  The aim of this thesis was to evaluate whether semaglutide can be used as an anti-obesity drug and the effect and safety of the substance compared with the already approved drug liraglutide.  The thesis is a literature study that uses five randomized clinical trials from the database PubMed. Of the six scientific articles, two examine liraglutide for 56 weeks, two semaglutide for 68 weeks and one both drugs for 52 weeks.  All studies demonstrate that semaglutide has a better effect on reducing body weight and waist measurement than liraglutide. In study 5, semaglutide above 1,4 mg per week is shown to have a statistically significantly better weight loss effect compared to liraglutide. Gastrointestinal side effects were the most common side effects in all included studies. The majority of these were of mild or moderate intensity. Of the gastrointestinal side effects, nausea was most common. In the semaglutide groups, the total side effects were slightly more frequent than in the liraglutide groups, which is mainly shown in study 5. Possible factors affecting the results is whether the participants receive IBT or lifestyle advice in combination with the treatment.  Conclusions that can be drawn from the studies is that semaglutide is more effective in terms of weight loss and reduction of waist measurements compared to liraglutide. The adverse reactions were generally similar between semaglutide and liraglutide. Semaglutide should currently be administered with caution and under supervision. More studies need to be conducted to control the dosage and safety.

This review details the manner in which the central nervous system regulates metabolic homeostasis in normal weight and obese rodents and humans. It includes a review of the homeostatic contributions of neurons located in the hypothalamus, the midbrain and limbic structures, the pons and the medullary area postrema, nucleus tractus solitarius, and vagus nucleus, and details how these brain regions respond to circulating levels of orexigenic hormones, such as ghrelin, and anorexigenic hormones, such as glucagon-like peptide 1 and leptin. It provides an insight as to how high intensity exercise may improve homeostatic control in overweight and obese subjects. Finally, it provides suggestions as to how further progress can be made in controlling the current pandemic of obesity and diabetes.

Introduction: Overweight and obesity are among the most serious public health problems in the world. Today, about half of adult men, one third of adult women and one in five children are estimated to be overweight or obese. Being overweight is not considered as a disease, but it can lead to obesity, which puts the individual at high risk of suffering from several diseases such as diabetes type 2, high blood pressure. To define whether an individual is overweight, normal weight, obese or underweight, BMI value is used. Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects women in fertitlity age. The syndrome is associated with several of risk factors such as insulin resistance, obesity, cardiovascular problems, and infertility. Imbalances in the hormones produced by ovaries can be a cause of PCOS.Currently, there are three prescription drugs in Sweden to treat obesity such as liraglutide (Saxenda®), bupropion/naltrexone (Mysimba®) and orlistat (Xenical®).Objectives: The purpose of this study was to investigate the effectiveness of using liraglutide as monotherapy or in combination with metformin to treat women who were overweight or obese and affected by polycystic ovarian syndrome.Method: This study is based on four randomized controlled clinical trials studies, which are taken from the PubMed database. Using these keywords “liraglutide, obesity, weight loss, BMI, treatment, metformin, PCOS”.Results: The greatest weight loss was observed in study 4 in obese women with PCOS, whichwere treated with the combination of both liraglutide 1.2 mg/day and metformin 1000 BID/day. A weight reduction of -9.23 ±1.23 after 12 weeks of treatment was observed. While less weight loss of -3.0 ± 0.6 kg was observed in study two, where obese women with PCOS were treated with liraglutide 1.2 mg/day and metformin 1000 mg BID/day as a monotherapy. In study 1, obese women with PCOS treated with the combination of both liraglutide 1.2-± mg/day and metformin 1000 BID/day had a weight loss of -6.5 ± 2.8 kg. The obese women with PCOS in study 3 were treated with liraglutide 3 mg/day and had a weight loss of -6.3 ± 3.7 kg butexperienced more severe GI adverse events.Conclusion: The four studies showed that short-term treatment with liraglutide, which is a GLP-1 receptor agonist, 1.2 mg/day together with metformin 1000 mg BID/day as a combination therapy is associated with significantly greater weight loss, BMI changes and with changes in waist circumference compared to when treated with liraglutide or metformin as a monotherapy

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Prediabetes is a condition affecting 35% of US adults and about 50% of US adults age 65+. Foods rich in polyphenols, including flavanols and other flavonoids, have been studied for their putative beneficial effects on many different health conditions including type 2 diabetes mellitus and prediabetes. Studies have shown that some flavanols increase glucagon-like peptide 1 (GLP- 1) levels. GLP-1 is a feeding hormone that increases insulin secretion after carbohydrate consumption and increased GLP-1 levels may be responsible for some of the beneficial effects on glycemic control after flavanol consumption. The present study explored the effects of grape powder consumption on metrics of glycemic health in normoglycemic and prediabetic C57BL/6J mice; additionally, the mechanism of action of grape powder was investigated. Grape powder significantly reduced (p<0.01) blood glucose levels following oral glucose gavage after GLP-1 receptor antagonism by exendin-3 (9-39) compared to sugar-matched control; indicating that it was able to attenuate the hyperglycemic effects of GLP-1 receptor antagonism. Grape powder was employed in acute (1.6 g grape powder/kg bodyweight) and long-term high fat diet (grape powder incorporated into treatment diets at 5% w/w) feeding studies in normoglycemic and prediabetic (diet-induced obesity) mice; grape powder did not improve glycemic control in these studies versus sugar-matched control. The mechanisms by which grape powder ameliorates the deleterious effects of GLP-1 receptor antagonism warrants further study. / Master of Science in Life Sciences

La greffe d’îlots pancréatiques est caractérisée par une réponse inflammatoire et procoagulante précoce, connue sous le nom d’IBMIR (Instant Blood Mediated Inflammatory Reaction). Les microparticules (MPs) porteuses de facteur tissulaire (TF) sont le témoin d’un important remodelage membranaire et constituent des acteurs centraux dans la dissémination du stress de l’IBMIR. Nous avons exploré l’effet d’un stress inflammatoire sur la survie et la fonction de la cellule β dans un modèle de communication cellulaire médiée par les MPs. La modulation pharmacologique par les analogues du GLP-1 a été évaluée, la par la mesure de la sécrétion d’insuline, de l’activité TF et l'analyse du remodelage de la membrane plasmique. Nos résultats décrivent les MPs comme des effecteurs autocrines et indiquent que les MPs sont des cibles potentielles pour les analogues du GLP-1 au cours de l'IBMIR. Les données apportent de nouvelles pistes sur les mécanismes cellulaires mis en jeu lors des phénomènes d’ischémie reperfusion durant l’IBMIR. / Pancreatic islets graft is characterized by early inflammatory and procoagulant events known as Instant Blood Mediated Inflammatory Reaction (IBMIR). Tissue factor (TF) bearing microparticles (MPs) are surrogates of important membrane remodeling and key players in the systemic and local dissemination of such stress.We investigated the effect of inflammatory stress on β cell survival and function in a MP-mediated cell crosstalk model. Pharmacological modulation by GLP-1 analogues was evaluated by measurement of insulin secretion, TF activity and assessment of plasma membrane remodeling. Our data evidenced MPs as autocrine effectors and possible new target for GLP-1 analogues. They bring new hints on the cellular mechanisms prompted by ischemia reperfusion during IBMIR.

[pt] O agonista do receptor do peptídeo semelhante ao glucagon 1 (GLP-1), melhora o controle glicêmico, reduz o apetite e o peso corporal, sendo usado para o tratamento de diabetes tipo 2 (DM2). Também se mostrou associado a alterações nas respostas cerebrais, relacionadas a estímulos alimentares. Entretanto, seus efeitos na conectividade funcional intrínseca do cérebro não são conhecidos. Com objetivo de melhor entender o papel do GLP-1 na conectividade intrínseca do cérebro em pacientes DM2, dados de ressonância magnética funcional (RMf) de redes do estado de repouso relevantes para o comportamento alimentar foram analisados em dois estudos. Em ambos, todas as imagens foram adquiridas após um jejum noturno (8-12 horas). O estudo 1 teve como meta investigar o efeito agudo do bloqueio de GLP-1 na conectividade funcional. Foram adquiridas imagens de RMf durante o estado de repouso, em dois dias separados, de 20 pacientes DM2 sem complicações e 20 controles saudáveis, primeiro sob infusão de solução salina e, posteriormente, sob a infusão de antagonista do receptor de GLP-1. Já o estudo 2 teve como objetivo investigar, em pacientes DM2, se haveria diferenças na conectividade intrínseca, quando comparados os tratamentos com agonista do GLP1 liraglutida e com insulina glargina. Os mesmos pacientes DM2, participantes do estudo 1, foram tratados, em ordem aleatória, por 12 semanas com liraglutida e por 12 semanas com insulina glargina. Os dados de RMf em estado de repouso foram coletados antes do início do tratamento, após 10 dias e após 12 semanas. As análises de neuroimagem foram corrigidas para múltiplas comparações com o Family-wise error, as correlações foram feitas com coeficiente de correlação de Pearson. Os resultados do estudo 1 mostraram que, durante a infusão da solução salina, pacientes DM2 apresentaram maior conectividade comparados a controles na ínsula esquerda e opérculo, relacionada à maior perda de peso, mediada pelo agonista de GLP-1 após 10 dias e 12 semanas. Além disso, a conectividade foi maior em pacientes DM2 versus controles no polo frontal, córtex frontal medial, no giro cingulado anterior e no giro paracingulado, a qual se correlacionou com menor perda de peso, mediada por agonista de GLP-1, após 10 dias (todos P(FWE) menor que 0,05). Não houve efeito da infusão do antagonista do receptor de GLP-1 ou do tratamento com agonista de GLP-1, na conectividade (todos P(FWE) maior que 0,05). Em conclusão, a conectividade basal em estado de repouso mostrou estar relacionada à mudança de peso, mediada pelo agonista do GLP-1, com maior conectividade frontal correlacionando com menos perda de peso durante o tratamento com agonista do GLP-1, enquanto maior conectividade na ínsula esquerda, correlacionou com maior perda de peso, mediada pelo GLP-1, indicando relação entre a conectividade intrínseca dessas redes e o efeito de perda de peso do tratamento com GLP-1. / [en] The glucagon-like peptide 1 (GLP-1) receptor agonist is used for the treatment of type 2 diabetes (DM2) as it improves glycemic control, reduces appetite and body weight. It is also related to altered brain responses to food stimuli, but its effects on intrinsic brain connectivity are unknown. With the goal of better understanding GLP-1 s role in the intrinsic brain connectivity of DM2 patients, functional resonance imaging (fMRI) data of resting-state networks relevant for eating behavior was analyzed in two studies. In both, all images were acquired after an overnight fast (8-12 hours). Study 1 aimed to investigate the acute effect of GLP1 blockade on functional connectivity. On two separate days, fMRI data was acquired from 20 DM2 patients and 20 healthy controls, first under saline infusion and thereafter under GLP-1 antagonist infusion. Study 2 aimed to investigate, in DM2 patients, if there were any between treatment differences in intrinsic connectivity when comparing GLP-1 receptor agonist liraglutide with insulin glargine. The same DM2 participants in study 1 were thus treated in random order for 12 weeks with liraglutide and insulin glargine, fMRI data was collected at the start of treatment, after 10 days and after 12 weeks. Study 1 results showed that, during saline infusion, DM2 patients had greater connectivity compared to controls in the left insula and operculum, which related to greater GLP-1 mediated weightloss after 10 days and 12 weeks. Also, connectivity was greater in DM2 patients versus controls in the frontal pole, frontal medial cortex, anterior cingulate and paracingulate giry, which related to less GLP-1 mediated weight-loss after 10 days (all P(FWE) less than 0.05). There was no effect on connectivity for GLP-1 antagonist, and no long-term differences between treatments (all P(FWE) less than 0.05). In conclusion, baseline resting-state connectivity was shown to be related to GLP-1 mediated weightchange, with greater frontal connectivity relating to less weight loss during GLP-1 treatment, while higher left insula connectivity correlated to greater weight loss during GLP-1 treatment, indicating a relationship between baseline intrinsic connectivity in these regions and weight loss during GLP-1 treatment.

L’homéostasie énergétique ou ‘balance énergétique’ est l’équilibre qui s’établit chez l’Homme et l’animal adulte entre la prise quotidienne de nutriments sous la forme de glucides, de lipides ou de protéines et leur oxydation pour ne produire que la quantité énergétique strictement nécessaire. Pour maintenir cette balance l’organisme doit recueillir en permanence des signaux nerveux, métaboliques ou hormonaux de la part de cellules spécifiques. Ces senseurs des besoins énergétiques transmettent alors à des centres régulateurs leurs informations qui en retour, par voie hormonale ou nerveuse, informent les organes effecteurs des mesures à prendre pour stocker, produire ou consommer l’énergie. Les trois principaux centres de cette balance sont 1/ le cerveau, centre intégrateur de l’information ; 2/ un groupe d’organes effecteurs parmi lesquels le foie, le tissu adipeux, les muscles squelettiques, le pancréas et 3/ un centre senseur de la qualité et de la quantité des aliments, le tractus gastrointestinal (Migrenne 2006). En plus d’être la source d’énergie nécessaire à la vie des cellules, les nutriments tels que les acides gras, le cholestérol ou encore le glucose sont aussi des molécules de signalisation cellulaire à la fois par leur fixation à des récepteurs membranaires mais aussi via des récepteurs nucléaires. Un déséquilibre dans l’homéostasie énergétique dû à une alimentation déséquilibrée, à un manque d’exercice physique ou à des facteurs génétiques est une caractéristique de l’obésité et de complications telles que le diabète de type 2 et les maladies cardiovasculaires (Hill, 2006). Au cours de ma thèse je me suis intéressé à l’intestin pour son rôle de régulateur de l’homéostasie énergétique dans un contexte physiologique ou physiopathologique d’obésité via sa capacité à sécréter l’incrétine Glucagon-Like Peptide-1 (GLP-1) en réponse au glucose et aux acides biliaires. J’ai étudié plus particulièrement le rôle du récepteur nucléaire en tant que senseurs moléculaires des acides biliaires FXR dans les cellules sécrétrices de cette incrétine car à l’heure actuelle rien n’était connu quant à son rôle ni même quant à son expression dans la cellule L. Pour cela, j’ai utilisé des lignées cellulaires murines et humaines où j’ai mis au point les conditions expérimentales pour répondre aux questions posées. Grâce à des ARN d’intestins issus de différents modèles de souris la relevance chez le rongeur a été testée. La relevance de ces résultats sur des biopsies intestinales humaine a également été testée. Grâce à ces outils, j'ai pu montré que FXR dans les cellules L était fonctionnel et que son activation interférait avec la voie de la glycolyse entrainant moins de synthèse et de sécrétion de GLP-1. Cela nous a permis de proposer un nouveau mécanisme moléculaire par lequel les séquestrants des acides biliaires exercent leur effets bénéfiques chez des patients atteints de diabète de type 2. / Originally identified as dietary lipid detergents, bile acids (BA) are now recognized as signaling molecules which bind to the transmembrane receptor TGR5 and the nuclear receptor FXR (Farnesoid X Receptor). Upon binding to TGR5 at the surface of enteroendocrine L cells, bile acids (BA) promote the secretion of the incretin GLP-1 which potentiates the glucose-induced insulin secretion by pancreatic beta-cells. More than 50% of the insulin secretion in response to glucose is mediated by GLP-1 and the other incretin Glucose-dependent Insulinotropic Polypeptide (GIP). Once secreted, GLP-1 is rapidly (2-3 minutes) degraded by the endothelial enzyme Dipeptydil Peptidase 4 (DPP4). GLP-1 analogues and DPP4 inhibitors are successfully used for the treatment of T2D. FXR is a ligand-activated nuclear receptor highly expressed in the liver and in the distal intestine. FXR controls BA, lipid and glucose metabolism. Whether FXR is expressed, functional in intestinal enteroendocrine L cells and in which extend its activation affects GLP-1 production are not yet reported. Encouraging data were obtained during my M2 training course. The aim of my thesis was thus to assess whether FXR in enteroendocrines cells could participate in the control of the deregulation of glucose homeostasis. Multiple in vitro, ex vivo and in vivo human and murine models allowed us to show that FXR is present and functional in L cells. FXR activation decreases GLP-1 production and secretion in L cells by inhibiting glycolysis pathway through an interference with the carbohydrate responsive transcription factor ChREBP. Finally, I identified an additional mechanism of action of the bile acid sequestrant Colesevelam, a molecule currently successfully used in USA for treating type 2 diabetic patients.