Cutaneous malignant melanoma in the Natal province : an epidemiologic study : reflections upon its aetiology.

Thesis (M.D.)-University of Natal, Durban, 1985.The purpose of the study has been primarily to draw a profile of malignant melanoma in the different population groups inhabiting the Natal Province and Kwa-Zulu, to compare the presentation and incidence of the disease between these groups as well as with similar racial groups in different countries. The data collected then permitted to estimate which parameters were relevant in predicting the course of the disease, as well as the results of surgical and adjuvant therapy, and was utilized in a search for the aetiology of the tumour

Is skeletal muscle mitochondrial dysfunction a cause or an indirect consequence of insulin resistance in humans?

The precise cause of insulin resistance and type 2 diabetes is unknown. However, there is a strong association between insulin resistance and lipid accumulation — and, in particular, lipotoxic fatty acid metabolites — in insulin-target tissues. Such accumulation is known to cause insulin resistance, particularly in skeletal muscle, by reducing insulin-stimulated glucose uptake. Reduced fat-oxidation capacity appears to cause such lipid accumulation and, over the past few years, many studies have concluded that decreased mitochondrial oxidative phosphorylation could be the initiating cause of lipid deposition and the development of insulin resistance. The aim of this review is to summarize the latest findings regarding the link between skeletal muscle mitochondrial dysfunction and insulin resistance in humans. At present, there are too few studies to definitively conclude that, in this context, mitochondria are functionally impaired (dysfunction in the respiratory chain). Indeed, insulin resistance could also be related to a decrease in the number of mitochondria or to a combination of this and mitochondrial dysfunction. Finally, we also consider whether or not these aberrations could be the cause of the development of the disease or whether mitochondrial dysfunction may simply be the consequence of an insulin-resistant state

Fatty liver and insulin resistance in obese Zucker rats: No role for mitochondrial dysfunction

The relationship between insulin resistance and mitochondrial function is of increasing interest. Studies looking for such interactions are usually made in muscle and only a few studies have been done in liver, which is known to be a crucial partner in whole body insulin action. Recent studies have revealed a similar mechanism to that of muscle for fat-induced insulin resistance in liver. However, the exact mechanism of lipid metabolites accumulation in liver leading to insulin resistance is far from being elucidated. One of the hypothetical mechanisms for liver steatosis development is an impairment of mitochondrial function. We examined mitochondrial function in fatty liver and insulin resistance state using isolated mitochondria from obese Zucker rats. We determined the relationship between ATP synthesis and oxygen consumption as well as the relationship between mitochondrial membrane potential and oxygen consumption. In order to evaluate the quantity of mitochondria and the oxidative capacity we measured citrate synthase and cytochrome c oxidase activities. Results showed that despite significant fatty liver and hyperinsulinemia, isolated liver mitochondria from obese Zucker rats display no difference in oxygen consumption, ATP synthesis, and membrane potential compared with lean Zucker rats. There was no difference in citrate synthase and cytochrome c oxidase activities between obese and lean Zucker rats in isolated mitochondria as well as in liver homogenate, indicating a similar relative amount of hepatic mitochondria and a similar oxidative capacity. Adiponectin, which is involved in bioenergetic homeostasis, was increased two-fold in obese Zucker rats despite insulin resistance. In conclusion, isolated liver mitochondria from lean and obese insulin-resistant Zucker rats showed strictly the same mitochondrial function. It remains to be elucidated whether adiponectin increase is involved in these results

Effects of the cannabinoid CB1 antagonist rimonabant on hepatic mitochondrial function in rats fed a high-fat diet

The aim of this study was to investigate the effect of rimonabant treatment on hepatic mitochondrial function in rats fed a high-fat diet. Sprague-Dawley rats fed a high-fat diet (35% lard) for 13 wk were treated with rimonabant (10 mg·kg−1·day−1) during the last 3 wk and matched with pair-fed controls. Oxygen consumption with various substrates, mitochondrial enzyme activities on isolated liver mitochondria, and mitochondrial DNA quantity were determined. Body weight and fat mass were decreased in rats treated with rimonabant compared with pair-fed controls. Moreover, the serum adiponectin level was increased with rimonabant. Hepatic triglyceride content was increased, while serum triglycerides were decreased. An increase of mitochondrial respiration was observed in rats treated with rimonabant. The increase of mitochondrial respiration with palmitoyl-CoA compared with respiration with palmitoyl-l-carnitine stating that the entry of fatty acids into mitochondria via carnitine palmitoyltransferase I was increased in rats treated with rimonabant. Moreover, rimonabant treatment led to a reduction in the enzymatic activity of ATP synthase, whereas the quantity of mitochondrial DNA and the activity of citrate synthase remained unchanged. To summarize, rimonabant treatment leads to an improvement of hepatic mitochondrial function by increasing substrate oxidation and fatty acid entry into mitochondria for the β-oxidation pathway and by increasing proton leak. However, this increase of mitochondrial oxidation is regulated by a decrease of ATP synthase activity in order to have only ATP required for the cell function

Dynamic regulation of mitochondrial network and oxidative functions during 3T3-L1 fat cell differentiation

Mitochondria have been shown to be impaired in insulin resistance-related diseases but have not been extensively studied during the first steps of adipose cell development. This study was designed to determine the sequence of changes of the mitochondrial network and function during the first days of adipogenesis. 3T3-L1 preadipocytes were differentiated into adipocytes without using glitazone compounds. At days 0, 3, 6, 9, and 12, mitochondrial network imaging, mitochondrial oxygen consumption, membrane potential, and oxidative phosphorylation efficiency were assessed in permeabilized cells. Gene and protein expressions related to fatty acid metabolism and mitochondrial network were also determined. Compared to preadipocytes (day 0), new adipocytes (days 6 and 9) displayed profound changes of their mitochondrial network that underwent fragmentation and redistribution around lipid droplets. Drp1 and mitofusin 2 displayed a progressive increase in their gene expression and protein content during the first 9 days of differentiation. In parallel with the mitochondrial network redistribution, mitochondria switched to uncoupled respiration with a tendency towards decreased membrane potential, with no variation of mtTFA and NRF1 gene expression. The expression of PGC1α and NRF2 genes and genes involved in lipid oxidation (UCP2, CD36, and CPT1) was increased. Reactive oxygen species (ROS) production displayed a nadir at day 6 with a concomitant increase in antioxidant enzyme gene expression. This 3T3-L1-based in vitro model of adipogenesis showed that mitochondria adapted to the increased number of lipid droplets by network redistribution and uncoupling respiration. The timing and regulation of lipid oxidation-associated ROS production appeared to play an important role in these changes

Perspectives and Potential Applications of Mitochondria-Targeted Antioxidants in Cardiometabolic Diseases and Type 2 Diabetes

There is abundant evidence to suggest that mitochondrial dysfunction is a main cause of insulin resistance and related cardiometabolic comorbidities. On the other hand, insulin resistance is one of the main characteristics of type 2 diabetes, obesity, and metabolic syndrome. Lipid and glucose metabolism require mitochondria to generate energy, and when O2 consumption is low due to inefficient nutrient oxidation, there is an increase in reactive oxygen species, which can impair different types of molecules, including DNA, lipids, proteins, and carbohydrates, thereby inducing proinflammatory processes. Factors which contribute to mitochondrial dysfunction, such as mitochondrial biogenesis and genetics, can also lead to insulin resistance in different insulin-target tissues, and its association with mitochondrial dysfunction can culminate in the development of cardiovascular diseases. In this context, therapies that improve mitochondrial function may also improve insulin resistance. This review explains mechanisms of mitochondrial function related to the pathological effects of insulin resistance in different tissues. The pathogenesis of cardiometabolic diseases will be explained from a mitochondrial perspective and the potential beneficial effects of mitochondria-targeted antioxidants as a therapy for modulating mitochondrial function in cardiometabolic diseases, especially diabetes, will also be considered.Contract grant sponsor: PI10/1195; Contract grant sponsor: PI 12/1984; Contract grant sponsor: CIBERehd CB06/04/0071; Contract grant sponsor: PROMETEO 2010/060; Contract grant sponsor: ACOMP/2012/042; Contract grant sponsor: ACOMP/2012/045; Contract grant sponsor: ACOMP2013/061; Contract grant sponsor: European Regional Development Fund (ERDF)

Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning

Obesity-related diseases such as diabetes and dyslipidemia result from metabolic alterations including the defective conversion, storage and utilization of nutrients, but the central mechanisms that regulate this process of nutrient partitioning remain elusive. As positive regulators of feeding behaviour, agouti-related protein (AgRP) producing neurons are indispensible for the hypothalamic integration of energy balance. Here, we demonstrate a role for AgRP-neurons in the control of nutrient partitioning. We report that ablation of AgRP-neurons leads to a change in autonomic output onto liver, muscle and pancreas affecting the relative balance between lipids and carbohydrates metabolism. As a consequence, mice lacking AgRP-neurons become obese and hyperinsulinemic on regular chow but display reduced body weight gain and paradoxical improvement in glucose tolerance on high-fat diet. These results provide a direct demonstration of a role for AgRP-neurons in the coordination of efferent organ activity and nutrient partitioning, providing a mechanistic link between obesity and obesity-related disorders

Métabolisme énergétique mitochondrial dans le développement de la stéatose hépatique

Hepatic steatosis is a pathology associated with obesity and insulin resistance. Mechanisms behind the development of hepatic steatosis are far from being elucidated. However, impaired mitochondrial function could contribute to the accumulation of lipids in the liver. Therefore, the objective of this work is to evaluate mitochondrial function in two animal models of fatty liver and the effects of two molecules, rimonabant and resveratrol. In a genetic model of obesity, Zucker rat, no alteration of the oxidative phosphorylation is observed. In a more physiological model, rats fed with a high fat diet during different time, in the first times of high fat diet, hepatic metabolism is oriented to use or store the fat excess. The first adjustment is then reversed and a decrease in the fatty acids oxidation but also a decrease in the storage of triglycerides are observed. Treatment with rimonabant in rats fed a high fat diet, has a beneficial effect on liver mitochondrial function especially by increasing fatty acids entry into the mitochondria and thus their oxidation. Finally, treatment with resveratrol in HepG2 cells, causes an increase in mitochondrial oxygen consumption and an increase in complex I activity, but without change in mitochondrial biogenesis. Although the mitochondria seems not much affected during the development of hepatic steatosis, considered it as a therapeutic target is still relevant.La stéatose hépatique est une pathologie associée à l'obésité et à l'insulinorésistance. Les mécanismes à l'origine du développement de la stéatose hépatique sont loin d'être élucidés. Cependant, une altération de la fonction mitochondriale pourrait contribuer à l'accumulation de lipides dans le foie. Par conséquent, l'objectif de ce travail est d'évaluer la fonction mitochondriale dans deux modèles animaux de stéatose hépatique ainsi que les effets de deux molécules, le rimonabant et le resvératrol. Dans un modèle génétique d'obésité, le rat Zucker, aucune altération de la phosphorylation oxydative n'est observée. Dans un modèle plus physiologique, le rat alimenté avec un régime riche en lipides pendant différentes durées, dans les premiers temps d'un apport accru en lipides, le métabolisme hépatique est orienté de manière à utiliser ou à stocker l'excès de lipides. Cette première adaptation est ensuite inversée et une diminution de l'oxydation des acides gras mais également une diminution du stockage de triglycérides sont observées. Le traitement avec du rimonabant de rats alimentés avec un régime en gras, a un effet bénéfique sur la fonction mitochondriale hépatique notamment en augmentant l'entrée des acides gras dans la mitochondrie et donc leur oxydation. Enfin, le traitement par du resvératrol de cellules HepG2, entraîne une augmentation de la consommation d'oxygène mitochondriale et une augmentation de l'activité du complexe I mais sans modification de la biogenèse mitochondriale. Même si la mitochondrie semble peu affectée au cours du développement de la stéatose hépatique, la considérer comme une cible thérapeutique reste pertinent

The official trips and the travels of public personalities in the East from the death of Alexander the Great to the beginning of the Roman Empire (323-30 B.C.) : between political ceremonial and cultural practice

A travers l’analyse des déplacements des souverains hellénistiques et des imperatores romains en Orient, ce travail entend éclairer le concept moderne de voyage officiel et démontrer la validité de cette catégorie pour caractériser les voyages de ces personnalités politiques antiques. Au-delà du critère du statut du voyageur, les sources mettent en lumière le rôle discriminant de l’infrastructure du voyage, ainsi que l’importance des procédures d’accueil public dans la reconnaissance collective de l’officiel. L’enquête conduit à souligner la dimension à la fois protocolaire et populaire de ce type de déplacement dont le caractère spectaculaire contribuait à assurer le retentissement exceptionnel pour en faire un [événement] local de grande ampleur. Manifestation de souveraineté, le voyage officiel s’inscrivait dans un processus de légitimation du pouvoir et constituait le cadre privilégié de la mise en scène de la personnalité politique : l’apparat et la théâtralisation du voyage autant que ses enjeux politiques majeurs peuvent être considérés comme des caractéristiques déterminantes du déplacement officiel. Cette réflexion pose également le problème de la pertinence de la dichotomie public/privé. Celle-ci n’est opératoire qu’à Rome où le concept de voyage fonctionnel est attesté, mais où l’on peut néanmoins observer une confusion entre la sphère de l’officium et celle de l’otium dans le cadre des déplacements des imperatores qui étaient l’occasion de démarches touristiques, culturelles ou religieuses révélatrices de la curiosité intellectuelle de ces personnages dont les séjours d’études puis les voyages officiels en Orient permettaient de satisfaire le philhellénisme.Through the analysis of the travels of the hellenistic kings and the roman imperatores in the East, this work intends to throw light on the modern concept of official trip and to demonstrate the validity of this category to characterize the travels of these ancient political personalities. Beyond the criterion of the status of the traveller, sources bring to light the discriminating role of the infrastructure of the trip, as well as the importance of public reception in the collective recognition of the official. The inquiry leads to underline the formal and the popular dimension of this kind of trip whose spectacular character contributed to ensure his exceptional impact and turn it into a large-scale local event. As a demonstration of [sovereignty], the official trip was part of a process of legitimization of power and provided the privileged framework for the staging of the political personality : the pageantry and dramatization of the journey as much as [its] major political stakes can be considered as distinctive characteristics of the official trip. This study also raises the problem of the relevance of the public/private dichotomy. The latter is only effective in Rome where the concept of functional trip is attested, but where a confusion of the sphere of the officium and the otium can nevertheless be observed within the travels of the imperatores which were the opportunity of touristic, cultural and religious initiatives revealing the intellectual curiosity of these characters whose study tours and official trips in the East made it possible to satisfy their philhellenism

The official trips and the travels of public personalities in the East from the death of Alexander the Great to the beginning of the Roman Empire (323-30 B.C.) : between political ceremonial and cultural practice

A travers l’analyse des déplacements des souverains hellénistiques et des imperatores romains en Orient, ce travail entend éclairer le concept moderne de voyage officiel et démontrer la validité de cette catégorie pour caractériser les voyages de ces personnalités politiques antiques. Au-delà du critère du statut du voyageur, les sources mettent en lumière le rôle discriminant de l’infrastructure du voyage, ainsi que l’importance des procédures d’accueil public dans la reconnaissance collective de l’officiel. L’enquête conduit à souligner la dimension à la fois protocolaire et populaire de ce type de déplacement dont le caractère spectaculaire contribuait à assurer le retentissement exceptionnel pour en faire un [événement] local de grande ampleur. Manifestation de souveraineté, le voyage officiel s’inscrivait dans un processus de légitimation du pouvoir et constituait le cadre privilégié de la mise en scène de la personnalité politique : l’apparat et la théâtralisation du voyage autant que ses enjeux politiques majeurs peuvent être considérés comme des caractéristiques déterminantes du déplacement officiel. Cette réflexion pose également le problème de la pertinence de la dichotomie public/privé. Celle-ci n’est opératoire qu’à Rome où le concept de voyage fonctionnel est attesté, mais où l’on peut néanmoins observer une confusion entre la sphère de l’officium et celle de l’otium dans le cadre des déplacements des imperatores qui étaient l’occasion de démarches touristiques, culturelles ou religieuses révélatrices de la curiosité intellectuelle de ces personnages dont les séjours d’études puis les voyages officiels en Orient permettaient de satisfaire le philhellénisme.Through the analysis of the travels of the hellenistic kings and the roman imperatores in the East, this work intends to throw light on the modern concept of official trip and to demonstrate the validity of this category to characterize the travels of these ancient political personalities. Beyond the criterion of the status of the traveller, sources bring to light the discriminating role of the infrastructure of the trip, as well as the importance of public reception in the collective recognition of the official. The inquiry leads to underline the formal and the popular dimension of this kind of trip whose spectacular character contributed to ensure his exceptional impact and turn it into a large-scale local event. As a demonstration of [sovereignty], the official trip was part of a process of legitimization of power and provided the privileged framework for the staging of the political personality : the pageantry and dramatization of the journey as much as [its] major political stakes can be considered as distinctive characteristics of the official trip. This study also raises the problem of the relevance of the public/private dichotomy. The latter is only effective in Rome where the concept of functional trip is attested, but where a confusion of the sphere of the officium and the otium can nevertheless be observed within the travels of the imperatores which were the opportunity of touristic, cultural and religious initiatives revealing the intellectual curiosity of these characters whose study tours and official trips in the East made it possible to satisfy their philhellenism