L’arthrose est une maladie dégénérative des articulations et représente la deuxième cause d’invalidité en France. En raison des liens entre l’obésité et l’arthrose concernant à la fois les articulations portantes et non portantes, nous faisons l’hypothèse que des protéines produites par le tissu adipeux, les adipokines, constituent des facteurs clés impliqués dans cette arthropathie. En premier lieu, nous avons montré que l’expression de la leptine, de l’adiponectine et de leurs récepteurs évolue de façon inverse et dépend fortement de l’état de différenciation des chondrocytes. Dans une seconde étude, nous avons comparé la production des adipokines par le ligament adipeux de Hoffa à celle mesurée dans la graisse sous-cutanée et avons ainsi mis en évidence des différences entre les 2 tissus adipeux. Les travaux réalisés ensuite ont permis de préciser le rôle des adipokines dans l’arthrose. Ainsi, la production d’adiponectine par les chondrocytes augmente lorsque le cartilage se dégrade et apparaît directement reliée à celle de la MMP-13 et du TGF-[bêta]. En revanche, l’expression de son récepteur AdipoR1 est associée à l’expression d’éléments matriciels et d’un facteur de transcription spécifique du cartilage impliqué dans la synthèse de ces éléments. Le traitement des chondrocytes à l’adiponectine a permis de confirmer in vitro les données observées in vivo chez les patients atteints d’arthrose, à savoir que l’adiponectine induit l’expression du TGF-[bêta]et de la MMP-13. Les résultats obtenus avec la leptine indiquent par ailleurs que l’obésité influence fortement la réponse des chondrocytes à cette adipokine. Elle semble ainsi protéger le cartilage chez les patients non obèses en stimulant l’expression de l’IGF-1, du collagène de type 2 et du TIMP-2, mais contribue au processus dégénératif chez les patients obèses en augmentant l’expression de la MMP-13. Enfin l’induction d’une arthrose expérimentale chez le rat Zucker n’ayant pas de récepteur fonctionnel à la leptine a montré que cette adipokine est susceptible de préserver l’articulation des modifications du cartilage et surtout de l’os sous-chondral / Osteoarthritis (OA) is a degenerative joint disease and represents one of the most frequent and disabling disease. There is a positive association between obesity and OA, and not only for knee joints but also for non-weight-bearing joints suggesting that adipose-derived proteins, namely adipokines, may be some keys factors in OA pathophysiology. First, we found that leptin and adiponectin expression and their receptor evolves in an opposite way and depend on differenciation stage of chondrocyte. The production of adipokines were then compared according to adipose tissue and some differences were found between, the infrapatellat fat pad and subcutaneous adipose tissue. After this work, we aimed to further characterize the role of leptin and adiponectin in OA. Adiponectin production by chondrocytes increases when cartilage is damaged and seems to be directly related with MMP-13 and TGF-[bêta] expression. AdipoR1 expression is associated with the expression of matrix components and with Sox9, a transcription factor involved in their synthesis. Adiponectin treatment confirms data in OA patient, that is adiponectin can induce TGF-[bêta] and MMP-13. Then, we showed obesity influences the chondrocyte responsivness to leptin. This adipokine seems to protect cartilage collected from normal or overweight patient by stimulating IGF-1, type 2 collagen and TIMP-2 expression while leptin increases MMP-13 expression for obese patients. Finally, experimental OA in Zucker rat deficient in leptin receptor, showed the protective effect of leptin on cartilage and on subchondral bone

Le syndrome métabolique (SM) augmente le risque de diabète et de maladies cardiovasculaires. Les composantes de cet état sont l’obésité, l’hypertension, le profil lipidique, la résistance à l’insuline, l’inflammation et l’atteinte hépatique. L’accumulation excessive de la masse grasse, surtout abdominale, entraîne une inflammation systémique de faible niveau. En effet, le tissu adipeux secrète des adipokines (leptine, visfatine, IL-6 et TNF-a) qui sont impliquées dans l’inflammation. Notre but a été d’étudier : 1) les associations de l’évolution de 5 ans de l’indice de masse corporelle (IMC) et de la leptine circulante avec les facteurs du SM et 2) l’expression de certaines adipokines dans les lymphocytes. Pour ces études, la cohorte STANISLAS a été un outil parfait (recueil des données sur les facteurs du SM, bio-banques : lymphocytes, sérum, plasma, ADN). L’étude longitudinale a démontré que certains de facteurs du SM évoluent ensemble au fil du temps et que ces groupes de facteurs sont liés à l’IMC en fonction du sexe. Ensuite, nous avons constaté des associations de la leptine avec des facteurs de risque du SM, différentes en fonction du sexe, indépendamment de la masse grasse. Enfin, nous avons détecté l’ARNm de nos adipokines et sa quantification a démontré des associations de la visfatine avec l’IMC et l’expression du TNF-a, et de la leptine avec la pression artérielle. L’ensemble de nos résultats souligne le rôle-médiateur de la leptine et l’impact du sexe sur les actions de cette hormone et ouvre de nouvelles perspectives pour étudier les adipokines dans le contexte de l’inflammation, en proposant un modèle d’étude : les lymphocytes. / The metabolic syndrome (MS) raises the risk for developing diabetes and cardiovascular disease. The components of this state are obesity, hypertension, disturbed lipid profile, insulin resistance, inflammation and hepatic steatosis. The excessive accumulation of fat mass, particularly in the abdomen, leads to low-grade systemic inflammation. Indeed, the adipose tissue produces adipokines such as leptin, visfatin, IL-6 and TNF-a that are implicated in the inflammatory processes. Our goal was to study: 1) the associations between 5 year-changes of the body mass index (BMI) and circulating leptin concentrations with the factors of the MS and 2) the expression of some adipokines in the lymphocytes. The STANISLAS cohort has enabled us to fulfil our research work (collection of a great number of data concerning MS factors, bio-banks: lymphocytes, serum, plasma, DNA). The longitudinal study on BMI changes and the factors associated with MS has shown that some of these factors evolve together (clusters) and that these groups of factors are associated with BMI changes in a sex dependent manner. We described also, associations of circulating leptin with MS factors, dependent to sex and independently of fat mass. Finally, we were able to detect and quantify mRNA of adipokines in lymphocytes. The quantification of the mRNA has shown associations of visfatin with BMI and gene expression of TNF-a and of leptin with blood pressure. The results obtained by this research work underline the mediating role of leptin and the impact of sex on the actions of this hormone and offers new perspectives for studying adipokines in the context of inflammation, by proposing a new model: PBMCs.

This study tested the ability of a novel adipose tissue derived cytokine, C1q TNF-related protein-3 (CTRP3), to prevent alcohol-induced hepatic lipid accumulation, or alcoholic fatty liver disease (ALD). Previous work has demonstrated that CTRP3 is effective at preventing high-fat diet-induced fatty liver; however, the potential of CTRP3 to inhibit ALD has not been explored. To test the potential protective effects of CTRP3, transgenic mice overexpressing CTRP3 (Tg) or wild-type littermates (WT) were subjected to one of two different models of ALD. In the first model, known as the NIAAA model, mice were fed control or alcohol-containing liquid diets (5% vol/vol) for 10 days followed by a single gavage of ethanol (5 g/kg). In the second model, the chronic model, mice were fed control or alcohol-containing diets for 6 wk with no gavage. This study found that CTRP3 reduced triglyceride accumulation in the chronic model of alcohol consumption by ~50%, whereas no reduction was observed in the NIAAA model. Further analysis of isolated primary hepatocytes from WT and Tg mice demonstrated that CTRP3 increased oxygen consumption in the presence of fatty acids, indicating that CTRP3 increases hepatic fatty acid utilization. In conclusion, this study indicates that CTRP3 attenuates hepatic triglyceride accumulation in response to long-term chronic, but not short-term, alcohol consumption.

Enlargement of adipocytes in obesity leads to alteration in adipokine production and these changes are linked to the development of obesity-related cardiovascular diseases. Adipokines specifically associated with obesity-related hypertension include angiotensinogen and adiponectin. Conjugated linoleic acid (CLA) has been reported to reduce blood pressure in obese insulin-resistant rats, but its mechanism of action has not been identified. The objective of this study was to determine whether CLA’s ability to improve obesity-related hypertension involves reducing adipocyte size and altering adipokine production. Fa/fa Zucker rats (6 or 16 week old) were fed diets containing CLA isomers for 8 weeks. The trans(t)10,cis(c)12-CLA isomer reduced adipocyte size in both younger and older rats. Despite beneficial changes in cell size of rats fed the t10,c12-CLA isomer, there were no changes in the renin-angiotensin system or pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 or the anti-inflammatory cytokine IL-10. In contrast, the t10,c12-CLA isomer increased adiponectin levels both in the circulation and in adipose tissue. This was associated with increased phosphorylation of endothelial nitric oxide synthase (eNOS) in adipose tissue and aorta. Direct treatment of CLA isomers in cultured endothelial cells did not increase eNOS phosphorylation but increases were observed with adiponectin treatment. In vivo, infusion with adiponectin increased eNOS phosphorylation in adipose of fa/fa Zucker rats in parallel with improvements in blood pressure. Similarly, when circulating levels of adiponectin increased in rats fed the t10,c12-CLA isomer diet, blood pressure was also attenuated. In younger rats, both the t10-c12 and c9,t11-CLA isomers were significantly different from the control group at week 8, however, only the t10,c12-CLA isomer was comparable to the commonly used anti-hypertensive medication captopril. In conclusion, the beneficial effects of the t10,c12-CLA isomer on blood pressure may in part be due to its ability to reduce the number of large adipocytes in vivo, thus increasing the production of adiponectin which subsequently activates vascular eNOS.

Dietary flaxseed has cardioprotective effects that may be achieved through its rich content of the omega-3 fatty acid, alpha linolenic acid (ALA). We investigated the effects of dietary flaxseed both with and without an atherogenic cholesterol-enriched diet to determine the effects of dietary flaxseed on the expression of the adipose cytokines leptin and adiponectin. Rabbits were fed one of four diets: a regular (RG) diet, or a regular diet with added 0.5% cholesterol (CH), or 10% ground flaxseed (FX), or both (CF) for 8 weeks. Levels of leptin and adiponectin expression were assessed by RT-PCR in visceral adipose tissue. Consumption of flaxseed significantly increased plasma and adipose levels of ALA. Leptin, but not adiponectin, mRNA expression was lower in CH animals and was elevated in CF animals. Changes in leptin expression were strongly and positively correlated with adipose ALA levels and inversely correlated with levels of en face atherosclerosis. Our data demonstrate that the type of fat in the diet as well as its caloric content can specifically influence leptin expression. The findings support the hypothesis that the beneficial cardiovascular effects associated with flaxseed consumption may be related to a change in leptin expression.

Enlargement of adipocytes in obesity leads to alteration in adipokine production and these changes are linked to the development of obesity-related cardiovascular diseases. Adipokines specifically associated with obesity-related hypertension include angiotensinogen and adiponectin. Conjugated linoleic acid (CLA) has been reported to reduce blood pressure in obese insulin-resistant rats, but its mechanism of action has not been identified. The objective of this study was to determine whether CLA’s ability to improve obesity-related hypertension involves reducing adipocyte size and altering adipokine production. Fa/fa Zucker rats (6 or 16 week old) were fed diets containing CLA isomers for 8 weeks. The trans(t)10,cis(c)12-CLA isomer reduced adipocyte size in both younger and older rats. Despite beneficial changes in cell size of rats fed the t10,c12-CLA isomer, there were no changes in the renin-angiotensin system or pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 or the anti-inflammatory cytokine IL-10. In contrast, the t10,c12-CLA isomer increased adiponectin levels both in the circulation and in adipose tissue. This was associated with increased phosphorylation of endothelial nitric oxide synthase (eNOS) in adipose tissue and aorta. Direct treatment of CLA isomers in cultured endothelial cells did not increase eNOS phosphorylation but increases were observed with adiponectin treatment. In vivo, infusion with adiponectin increased eNOS phosphorylation in adipose of fa/fa Zucker rats in parallel with improvements in blood pressure. Similarly, when circulating levels of adiponectin increased in rats fed the t10,c12-CLA isomer diet, blood pressure was also attenuated. In younger rats, both the t10-c12 and c9,t11-CLA isomers were significantly different from the control group at week 8, however, only the t10,c12-CLA isomer was comparable to the commonly used anti-hypertensive medication captopril. In conclusion, the beneficial effects of the t10,c12-CLA isomer on blood pressure may in part be due to its ability to reduce the number of large adipocytes in vivo, thus increasing the production of adiponectin which subsequently activates vascular eNOS.

Dietary flaxseed has cardioprotective effects that may be achieved through its rich content of the omega-3 fatty acid, alpha linolenic acid (ALA). We investigated the effects of dietary flaxseed both with and without an atherogenic cholesterol-enriched diet to determine the effects of dietary flaxseed on the expression of the adipose cytokines leptin and adiponectin. Rabbits were fed one of four diets: a regular (RG) diet, or a regular diet with added 0.5% cholesterol (CH), or 10% ground flaxseed (FX), or both (CF) for 8 weeks. Levels of leptin and adiponectin expression were assessed by RT-PCR in visceral adipose tissue. Consumption of flaxseed significantly increased plasma and adipose levels of ALA. Leptin, but not adiponectin, mRNA expression was lower in CH animals and was elevated in CF animals. Changes in leptin expression were strongly and positively correlated with adipose ALA levels and inversely correlated with levels of en face atherosclerosis. Our data demonstrate that the type of fat in the diet as well as its caloric content can specifically influence leptin expression. The findings support the hypothesis that the beneficial cardiovascular effects associated with flaxseed consumption may be related to a change in leptin expression.

Adaptace na chronickou hypoxii zvyšuje toleranci srdce k ischemicko-reperfuznímu poškození. Tato adaptace je umožněna řadou fyziologických změn na buněčné úrovni. Jednou z nich je změna v buněčném energetickém metabolismu. Tento proces může být regulován proteinem FTO (z angl. fat mass and obesity associated), demetylázou epigeneticky regulující buněčnou syntézu proteinů. Srdeční metabolismus může být také modulován adipokiny leptinem a adiponektinem. Cílem tohoto projektu bylo proto studovat roli FTO a adipokinů v chronicky hypoxickém srdci. Dospělí samci potkanů kmene Sprague Dawley byli adaptováni na dva modely kontinuální normobarické hypoxie (CNH; 12 % O2 a 10 % O2; 3 týdny). CNH (10 % O2) redukovala u těchto zvířat rozsah infarktu myokardu o 20 %. CNH (12 % O2) nebyla kardioprotektivní. Hladina proteinu FTO byla měřena v tkáni levých (LV) a pravých (RV) komor, stejně jako v játrech a koncovém mozku hypoxických i normoxických zvířat. Za normoxie je hladina FTO v RV o 50 % vyšší než v LV. Ve vysoce metabolicky aktivních tkáních jater a koncového mozku jsou pak hladiny FTO vyšší dokonce 6krát a 11krát. CNH (12 % O2) vedla k signifikantnímu nárůstu hladiny proteinu FTO v srdci. Jednalo se o 21% nárůst v LV a 27% v RV. Hladiny v játrech a koncových mozcích nebyly CNH ovlivněny. Silnější CNH (10 % O2)...

Fibroblast Growth Factor 21 (FGF21) is a hormone that is produced from the liver which has pleiotropic effects. Physiologically, FGF21 increases energy expenditure, increases glucose uptake, enhances glucose tolerance, and increases peripheral insulin sensitivity. Pharmacologically, FGF21 reverses obesity and diabetes in animal models and significantly improves metabolic profiles in humans through unknown mechanisms. We hypothesized that the physiological actions of FGF21 may provide insights to explain FGF21’s beneficial pharmacological effects. The overall theme of this work was to identify the elusive mechanism by which FGF21 regulates energy homeostasis. In chapter 1, I review some adipokines and hepatokines that regulate energy homeostasis. In chapter 2, I provide background on fibroblast growth factors (FGFs), metabolic FGFs, and the tissue-specific effects of FGF21. In chapter 3, I will review the role of growth factors in thermoregulation. In chapter 4, we use tissue-specific loss of function models to investigate the trajectory of FGF21’s thermogenic effects during prolonged cold. In chapter 5, we specifically address the necessity and sufficiency of FGF21 signaling directly to adipose tissue, and the contribution of the adipokine adiponectin in mediating FGF21’s metabolic effects. In chapter 6, I summarize our results, reflect upon the ramifications of these results, and briefly address potential future experiments given our results on the physiological and pharmacological actions of FGF21 in adipose tissues.

No description available.