Studies have suggested the possibility that there is sensory (SS) afferent signaling from white adipose tissue (WAT) to the brain, which may play an important role in communication with the brain sympathetic nervous system (SNS) outflow to WAT. Therefore, we tested whether the SNS-SS feedback loop between the subcutaneous inguinal WAT (IWAT) and the epididymal WAT (EWAT) exists. These fat pads were chosen due to 1) their divergent role in manifestation of metabolic disorders with the IWAT being beneficial and the EWAT being detrimental, as well as 2) different lipolytic response to glucoprivic 2-deoxyglucose (2DG). By using retrograde tract tracers Fast Blue (FB) and Fluorogold (FG), we found that the IWAT is more innervated than EWAT by both the SS and SNS ganglia (T13-L3). Surprisingly, we found ~12-17% of double-labeled cells in the SNS and SS ganglia innervating fat depots, implying SNS-SS crosstalk loops between the IWAT and EWAT. Increased neuronal activation by 2DG was observed in the SNS ganglia to both IWAT and EWAT but not in the SS dorsal root ganglia. In addition, 2DG induced lipolysis in both fat pads with greater lipolytic properties in the IWAT as a result of higher density of the SNS-SS fibers. Collectively, our results show neuroanatomical reality of the IWAT and EWAT SNS-SS neural crosstalk with a coordinated control of lipolytic function.

Le traitement de référence de la maladie de Parkinson (MP) reste l’utilisation du précurseurdirect de la dopamine: la L-3,4-dihydroxyphenylalanine (L-Dopa). Le traitement chroniquedes patients parkinsoniens à la L-Dopa induit, en revanche, systématiquement desmouvements involontaires anormaux que l’on qualifie de dyskinésies induites par la L-Dopa(DIL). L’étude de l’expression des dyskinésies s’est essentiellement focalisée sur lesdysfonctions neuronales engendrées dans les régions motrices des ganglions de la base et apermis de révéler une surexpression significative de gènes de réponse précoce (GRP) tels que: ΔFosB, ARC, Zif268 et FRA2 dans le striatum de rats dyskinétiques traités chroniquement à la L–Dopa. En revanche, plusieurs autres régions dopaminoceptives, probablement affectées par la dopamine exogène nouvellement synthétisée, ont été négligées alors qu’elles pourraient jouer un rôle clé dans l’expression des dyskinésies. Par conséquent, nous avons quantifié l’expression de ΔFosB, ARC, FRA2 et Zif268 dans l’ensemble du cerveau de rats dyskinétiques que nous avons comparée à des rats non-dyskinétiques. Cette approche nous a permis d’identifier 9 structures, localisées en dehors des ganglions de la base, présentant une surexpression d’au moins 3 des GRPs cités ci-dessus. Parmi ces structures, le domaine dorsolatéral du « bed nucleus of the stria terminalis » (dlBST) et l’habenula latérale (LHb) montrent une corrélation significative entre l’expression de ΔFosB et la sévérité des dyskinésies. Nous avons donc fait l’hypothèse que ces 2 structures pouvaient être impliquées dans l’expression des dyskinésies. Par conséquent, pour évaluer le rôle potentiel du dlBST et de la LHb dans les dyskinésies, nous avons inhibé l’activité électrique des neurones exprimant FosB/ΔFosB en utilisant la méthode d’inactivation sélective du Daun02/ß-galactosidase que nous avons précédemment validée dans une structure bien connue pour être impliquée dans les dyskinésies: le striatum. Nous avons démontré que l’inhibition de ces neurones, à la fois dans le dlBST et la LHb, diminuait la sévérité des dyskinésies sans affecter l’effet bénéfique de la L-Dopa chez les rats dyskinétiques. Nous avons ensuite pu confirmer l’implication du dlBST grâce au model de référence des dyskinésies: le macaque dyskinétique lésé au MPTP. L’ensemble de ces résultats nous a ainsi permis de montrer, pour la première fois, l’implication fonctionnelle de 2 structures externes aux ganglions de la base dans l’expression des dyskinésies, offrant de nouvelles perspectives thérapeutiques. / The gold standard treatment for Parkinson’s disease (PD) remains the dopamine precursor L- 3,4-dihydroxyphenylalanine (L-Dopa). Long-term L-Dopa treatment systematically leads to abnormal involuntary movements (AIMs) called L-Dopa-induced dyskinesia (LID). These manifestations first led to investigate the neuronal dysfunctions in the motor regions of thebasal ganglia and unravelled an overexpression of ΔFosB, ARC, Zif268 and FRA2 immediate-early genes (IEG) in the dopamine-depleted striatum of dyskinetic rats. However, other several dopaminoceptive structures, likely affected by the exogenously produced dopamine, have been neglected although they might play a key role in mediating LID. Hence, we assessed the expression of ΔFosB, ARC, FRA2 and Zif268 IEGs in the whole brain of dyskinetic rats compared to non-dyskinetic ones. Such approach shed light notably upon 9 structures located outside of the basal ganglia displaying an IEG overexpression. Among them, the dorsolateral bed nucleus of the stria terminalis (dlBST) and the lateralhabenula (LHb) displayed a significant correlation between ΔFosB expression and LID severity. We therefore postulated that these structures might play a role in LID manifestation. Therefore, to assess dlBST and LHb causal roles upon LID severity, we inhibited the electrical activity of FosB/ΔFosB-expressing neurons using the selective Daun02/β- galactosidase inactivation method that we previously validated in a well known structure involve in LID: the striatum. Interestingly, the inactivation of dlBST and LHb ΔfosBexpressing neurons alleviated LID severity and increased the beneficial effect of L-Dopa in dyskinetic rats. Remarkably, BST involvement in LID was confirmed in the gold standard model of LID, the dyskinetic MPTP-lesioned macaque. Altogether, our results highlight for the first time the functional involvement of 2 structures.

Introdução: O miocárdio não-compactado é uma doença genética rara de fisiopatologia desconhecida e controversa. Vários fatores têm sido implicados na fisiopatologia, como a disfunção da microcirculação, a perda da torção ventricular, distúrbios mitocondriais e mutações. A alteração do metabolismo cardíaco ocorre precocemente a disfunção diastólica e sistólica, reforçando a relevância desse estudo na análise combinada de tomografia de emissão de pósitron (PET) com 18F-Fluor-2-desoxiglicose e cintilografia de perfusão miocárdica com 99mTc-sestamibi pela tomografia por emissão de fóton simples (SPECT) e suas implicações clínicas. Métodos: Trinta pacientes com miocárdio não-compactado (41 ± 12 anos, 53% do sexo masculino), diagnosticados pelos critérios da ressonância magnética cardíaca, e 8 indivíduos saudáveis (42 ± 12 anos, 50% do sexo masculino) foram recrutados prospectivamente para serem submetidos a análise de perfusão miocárdica pelo SPECT e da captação miocárdica de glicose marcada pela PET. Resultados: Os pacientes apresentaram valores de captação de glicose miocárdica (CMG) menor que os controles (36.9 +- 8.8 vs. 44.6 +- 5.4 umol/min/100g, respectivamente, P = 0.02). Analisando a captação nos 17 segmentos de ambos os grupos, a CGM foi significativamente reduzida em 8 segmentos dos pacientes (P < 0,05). A diferença da média da captação miocárdica de glicose de todos os segmentos do grupo controle em relação a média dos segmentos compactados dos pacientes foi de 8,3 ?mol/min/100g (p < 0,001). Déficit de perfusão foi demonstrado em 15 (50%) dos pacientes, correspondendo a 45 segmentos do ventrículo esquerdo, destes 64,4% com padrão match e 35,6% com padrão mismatch pela análise de perfusão e metabolismo cardíaco. Nas análises univariada e multivariada foram observadas que o betabloqueador aumenta a CMG (coeficiente beta = 10.1, P = 0.008), como também ocorre um aumento gradual da CMG naqueles com doses mais elevadas (P para tendência linear = 0.01). Conclusão: A redução da captação miocárdica de glicose suporta a hipótese de que um mecanismo metabólico celular possa ter um papel na fisiopatologia do miocárdio não compactado. O betabloqueador demonstrou um efeito incremental dosedependente na captação miocárdica de glicose nos pacientes com miocárdio não-compactado, essa modulação do substrato cardíaco necessita de mais estudos para comprovação do benefício clínico nessa população / Background: Noncompaction cardiomyopathy (NCC) is a rare genetic disease with unknown and controversial pathophysiology. Several factors have been implicated such as microvascular dysfunction, loss of ventricular torsion, mitochondrial disorders, and genetic mutations. The change in cardiac metabolism occurs before the diastolic and systolic dysfunction, reinforcing the relevance of this study by the combined analysis of positron emission tomography with 18F-Fluor-2-deoxyglucose (PET) and myocardial perfusion scintigraphy with 99mTc-sestamibi by single-photon emission computed tomography (SPECT) and their clinical implications. Methods: Thirty patients (41 ± 12 years, 53% male) with NCC, diagnosed by cardiovascular magnetic resonance criteria, and 8 age-matched healthy controls (42 ± 12 years, 50% male) were prospectively recruited to undergo FDG-PET with measurement of the myocardial glucose uptake rate (MGU) and SPECT in order to investigate perfusion-metabolism patterns. Result: Patients with LVNC had lower global MGU compared with that in controls (36.9 +- 8.8 vs. 44.6 +- 5.4 +-mol/min/100g, respectively, P = 0.02). Of 17 LV segments, MGU levels were significantly reduced in 8, and also a reduction was observed when compacted segments from LVNC were compared with the segments from control subjects (P < 0,05). The difference in mean myocardial glucose uptake of all segments of the control group compared to the mean of the compact segments of the patients was 8.3 ?mol/min/100g (p < 0,001). Perfusion defects were also found in 15 (50%) patients (45 LV segments: 64.4% match, and 35.6% mismatch perfusionmetabolism pattern). Univariate and multivariate analyses showed that betablocker therapy was associated with increased MGU (beta coefficient=10.1, P = 0.008). Moreover, a gradual increase occurred in MGU across the beta-blocker dose groups (P for trend = 0.01). Conclusions: The reduction of MGU documented by FDG-PET in LVNC supports the hypothesis that a cellular metabolic pathway may play a role in the pathophysiology of LVNC. Betablocker demonstrated an incremental dose-dependent effect on myocardial glucose uptake in patients with NCC. The beneficial effect of beta-blocker mediating myocardial metabolism in the clinical course of LVNC requires further investigation

L’absence de réponse et la résistance des cellules cancéreuses mammaires aux thérapies actuelles justifient de développer de nouveaux traitements. Une stratégie prometteuse consiste à cibler le métabolisme énergétique des cellules cancéreuses. Dans ce contexte, des thiazolidinediones (TZD) présentent des effets antiprolifératifs qui pourraient résulter d’une atteinte du métabolisme énergétique. Notre laboratoire étudie des TZD dérivées de la troglitazone (TGZ). Durant cette thèse, nous avons cherché à déterminer si la Δ2-Troglitazone (Δ2-TGZ) modifie le métabolisme énergétique des cellules cancéreuses mammaires. Jusqu’à présent, les expériences menées au laboratoire étaient réalisées dans un milieu de culture contenant 1% de sérum de veau fœtal (SVF) qui crée un stress peu propice à l’étude du métabolisme. Nous avons donc d’abord caractérisé les effets de la Δ2-TGZ dans un milieu de culture contenant 10% SVF. Dans ces conditions, la Δ2-TGZ diminue toujours la prolifération des cellules cancéreuses mammaires, mais les doses requises sont plus élevées. En outre, la Δ2-TGZ induit des effets cytostatiques plutôt que l’apoptose. Nous avons ensuite montré que la Δ2-TGZ induit une perturbation du métabolisme énergétique, consistant en un blocage de la respiration mitochondriale que les cellules semblent compenser en stimulant la glycolyse. En parallèle, nous avons caractérisé le mode d’action du 2-désoxyglucose dont l’action antiproliférative dans les cellules cancéreuses mammaires est due à l’inhibition de la glycolyse et à la perturbation de la N-glycosylation des protéines. Il reste à déterminer la part des altérations métaboliques dans l’action anti-cancéreuse de la Δ2-TGZ / The absence of response and the resistance of cancer cells to therapies are strong arguments for the development of new therapeutic strategies. Data from the literature suggest that it could be interesting to target energy metabolism of cancer cells. In this context, thiazolidinediones (TZDs) display antiproliferative effects that could be the result of energy metabolism alteration. During this PhD, we aimed at determining if Δ2-Troglitazone (Δ2-TGZ) could modify energy metabolism of breast cancer cells. The experiments performed previously used a culture medium containing 1% of fetal calf serum (FCS) that is rather a stress inducing condition that can disturb cell metabolism. Thus, we first characterized the effects of Δ2-TGZ in a 10% FCS containing medium. In this case, Δ2-TGZ still decreases cell proliferation of breast cancer cells, but it requires high doses. Besides, Δ2-TGZ induces cell cycle arrest instead of apoptosis. Then, we have shown that Δ2-TGZ induced modifications of energy metabolism, which are due to a decrease in oxidative phosphorylation. We also observed an increase in glycolytic activity that is probably a compensatory mechanism. During this part of our work, we have also characterized the mechanisms involved in the anticancer activity of 2-deoxyglucose. We have shown that in breast cancer cells, this compound acts not only by glycolysis inhibition but also by protein N-glycosylation alteration. We have now to determine the part of metabolic alterations that are involved in the anti-cancer effects of Δ2-TGZ

Introdução: O miocárdio não-compactado é uma doença genética rara de fisiopatologia desconhecida e controversa. Vários fatores têm sido implicados na fisiopatologia, como a disfunção da microcirculação, a perda da torção ventricular, distúrbios mitocondriais e mutações. A alteração do metabolismo cardíaco ocorre precocemente a disfunção diastólica e sistólica, reforçando a relevância desse estudo na análise combinada de tomografia de emissão de pósitron (PET) com 18F-Fluor-2-desoxiglicose e cintilografia de perfusão miocárdica com 99mTc-sestamibi pela tomografia por emissão de fóton simples (SPECT) e suas implicações clínicas. Métodos: Trinta pacientes com miocárdio não-compactado (41 ± 12 anos, 53% do sexo masculino), diagnosticados pelos critérios da ressonância magnética cardíaca, e 8 indivíduos saudáveis (42 ± 12 anos, 50% do sexo masculino) foram recrutados prospectivamente para serem submetidos a análise de perfusão miocárdica pelo SPECT e da captação miocárdica de glicose marcada pela PET. Resultados: Os pacientes apresentaram valores de captação de glicose miocárdica (CMG) menor que os controles (36.9 +- 8.8 vs. 44.6 +- 5.4 umol/min/100g, respectivamente, P = 0.02). Analisando a captação nos 17 segmentos de ambos os grupos, a CGM foi significativamente reduzida em 8 segmentos dos pacientes (P < 0,05). A diferença da média da captação miocárdica de glicose de todos os segmentos do grupo controle em relação a média dos segmentos compactados dos pacientes foi de 8,3 ?mol/min/100g (p < 0,001). Déficit de perfusão foi demonstrado em 15 (50%) dos pacientes, correspondendo a 45 segmentos do ventrículo esquerdo, destes 64,4% com padrão match e 35,6% com padrão mismatch pela análise de perfusão e metabolismo cardíaco. Nas análises univariada e multivariada foram observadas que o betabloqueador aumenta a CMG (coeficiente beta = 10.1, P = 0.008), como também ocorre um aumento gradual da CMG naqueles com doses mais elevadas (P para tendência linear = 0.01). Conclusão: A redução da captação miocárdica de glicose suporta a hipótese de que um mecanismo metabólico celular possa ter um papel na fisiopatologia do miocárdio não compactado. O betabloqueador demonstrou um efeito incremental dosedependente na captação miocárdica de glicose nos pacientes com miocárdio não-compactado, essa modulação do substrato cardíaco necessita de mais estudos para comprovação do benefício clínico nessa população / Background: Noncompaction cardiomyopathy (NCC) is a rare genetic disease with unknown and controversial pathophysiology. Several factors have been implicated such as microvascular dysfunction, loss of ventricular torsion, mitochondrial disorders, and genetic mutations. The change in cardiac metabolism occurs before the diastolic and systolic dysfunction, reinforcing the relevance of this study by the combined analysis of positron emission tomography with 18F-Fluor-2-deoxyglucose (PET) and myocardial perfusion scintigraphy with 99mTc-sestamibi by single-photon emission computed tomography (SPECT) and their clinical implications. Methods: Thirty patients (41 ± 12 years, 53% male) with NCC, diagnosed by cardiovascular magnetic resonance criteria, and 8 age-matched healthy controls (42 ± 12 years, 50% male) were prospectively recruited to undergo FDG-PET with measurement of the myocardial glucose uptake rate (MGU) and SPECT in order to investigate perfusion-metabolism patterns. Result: Patients with LVNC had lower global MGU compared with that in controls (36.9 +- 8.8 vs. 44.6 +- 5.4 +-mol/min/100g, respectively, P = 0.02). Of 17 LV segments, MGU levels were significantly reduced in 8, and also a reduction was observed when compacted segments from LVNC were compared with the segments from control subjects (P < 0,05). The difference in mean myocardial glucose uptake of all segments of the control group compared to the mean of the compact segments of the patients was 8.3 ?mol/min/100g (p < 0,001). Perfusion defects were also found in 15 (50%) patients (45 LV segments: 64.4% match, and 35.6% mismatch perfusionmetabolism pattern). Univariate and multivariate analyses showed that betablocker therapy was associated with increased MGU (beta coefficient=10.1, P = 0.008). Moreover, a gradual increase occurred in MGU across the beta-blocker dose groups (P for trend = 0.01). Conclusions: The reduction of MGU documented by FDG-PET in LVNC supports the hypothesis that a cellular metabolic pathway may play a role in the pathophysiology of LVNC. Betablocker demonstrated an incremental dose-dependent effect on myocardial glucose uptake in patients with NCC. The beneficial effect of beta-blocker mediating myocardial metabolism in the clinical course of LVNC requires further investigation

No description available.

No description available.