Modélisation mathématique de la régulation hormonale de la prise alimentaire et de la prise de poids : Applications à la restriction calorique et la résistance à la leptine

The regulation of food intake and energy expenditure usually limits important loss or gain of body weight. Hormones (leptin, ghrelin, insulin) and nutrients (glucose, triglycerides) are among the main regulators of food intake. Leptin is also involved in leptin resistance, often associated with obesity and characterized by a reduced efficacy to regulate food intake. Mathematical models describing the dynamics of body weight have been used to assist clinical weight loss interventions or to study an experimentally inaccessible phenomenon, such as starvation experiments in humans. Modeling of the effect of hormones on body weight has however been largely ignored.In this thesis, we first consider a model of body weight regulation by hormones in rats, made of nonlinear differential equations. It describes the dynamics of food intake, body weight and energy expenditure, regulated by leptin, ghrelin and glucose. It is able to reproduce and predict the evolution of body weight and food intake in rats submitted to different patterns of caloric restriction, showing the importance of the adaptation of energy expenditure. Second, we introduce the first model of leptin resistance development, based on the regulation of food intake by leptin and leptin receptors. We show that healthy individuals may become leptin resistant and obese due to perturbations in food intake or leptin concentration. Finally, modifications of these models are presented, characterized by simplified yet realistic body weight dynamics. The models prove able to fit the previous, as well as new sets of experimental data and allow to build a complete model combining both previous models regulatory mechanismsRéguler la prise alimentaire et la dépense énergétique permet en général de limiter d'importants changements de poids corporel. Hormones (leptine, ghréline, insuline) et nutriments sont impliqués dans ces régulations. La résistance à la leptine, souvent associée à l'obésité, limite la régulation de la prise alimentaire. La modélisation mathématique de la dynamique du poids contribue en particulier à une meilleure compréhension des mécanismes de régulation (notamment chez l’humain). Or les régulations hormonales sont largement ignorées dans les modèles existants.Dans cette thèse, nous considérons un modèle de régulation hormonale du poids appliqué aux rats, composé d'équations différentielles non-linéaires. Il décrit la dynamique de la prise alimentaire, du poids et de la dépense énergétique, régulés par la leptine, la ghréline et le glucose. Il reproduit et prédit l'évolution du poids et de la prise alimentaire chez des rats soumis à différents régimes hypocaloriques, et met en évidence l'adaptation de la dépense énergétique. Nous introduisons ensuite le premier modèle décrivant le développement de la résistance à la leptine, prenant en compte la régulation de la prise alimentaire par la leptine et ses récepteurs. Nous montrons que des perturbations de la prise alimentaire, ou de la concentration en leptine, peuvent rendre un individu sain résistant à la leptine et obèse. Enfin, nous présentons une simplification réaliste de la dynamique du poids dans ces modèles, permettant de construire un nouveau modèle combinant les deux modèles précédent

A predictive model of the dynamics of body weight and food intake in rats submitted to caloric restrictions.

International audienceDynamics of body weight and food intake can be studied by temporally perturbing food availability. This perturbation can be obtained by modifying the amount of available food over time while keeping the overall food quantity constant. To describe food intake dynamics, we developed a mathematical model that describes body weight, fat mass, fat-free mass, energy expenditure and food intake dynamics in rats. In addition, the model considers regulation of food intake by leptin, ghrelin and glucose. We tested our model on rats experiencing temporally variable food availability. Our model is able to predict body weight and food intake variations by taking into account energy expenditure dynamics based on a memory of the previous food intake. This model allowed us to estimate this memory lag to approximately 8 days. It also explains how important variations in food availability during periods longer than these 8 days can induce body weight gains

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

A mathematical model of leptin resistance

International audienceObesity is often associated with leptin resistance, which leads to a physiological system with high leptin concentration but unable to respond to leptin signals and to regulate food intake. We propose a mathematical model of the leptin-leptin receptors system, based on the assumption that leptin is a regulator of its own receptor activity, and investigate its qualitative behavior. Based on current knowledge and previous models developed for body weight dynamics in rodents, the model includes the dynamics of leptin, leptin receptors and the regulation of food intake and body weight. It displays two stable equilibria, one representing a healthy state and the other one an obese and leptin resistant state. We show that a constant leptin injection can lead to leptin resistance and that a temporal variation in some parameter values influencing food intake can induce a change of equilibrium and a pathway to leptin resistance and obesity

A general mathematical model for the in vitro assembly dynamics of intermediate filament proteins

International audienceIntermediate filament (IF) proteins assemble into highly flexible filaments that organize into complex cytoplasmic networks: keratins in all types of epithelia, vimentin in endothelia and desmin in muscle. Since IF elongation proceeds via end-to-end annealing of unit-length filaments and successively of progressively growing filaments, it is important to know, how their remarkable flexibility, i.e., their persistence length l(p), influences the assembly kinetics. In fact, their l(p) ranges between 0.3 μm (keratin K8/K18) and 1.0 μm (vimentin and desmin), and thus is orders of magnitude lower than that of microtubules and F-actin. Here, we present a unique mathematical model, which implements the semiflexible nature of the three IF types based on published semiflexible polymers theories and depends on a single free parameter k(0). Calibrating this model to filament mean length dynamics of the three proteins, we demonstrate that the persistence length is indeed essential to accurately describe their assembly kinetics. Furthermore, we reveal that the difference in flexibility alone does not explain the significantly faster assembly rate of keratin filaments compared to that of vimentin. Likewise, desmin assembles ∼ six times faster than vimentin, even though both their filaments exhibit the same l(p) value. These data strongly indicate that differences in their individual amino acid sequences significantly impact the assembly rates. Nevertheless, using a single k(0) value for each of these three key representatives of the IF protein family, our advanced model does accurately describe the length distribution and mean length dynamics and provides effective filament assembly rates. It thus provides a tool for future investigations on the impact of post-translational modifications or amino acid changes of IF proteins on assembly kinetics. This is an important issue, as the discovery of mutations in IF genes causing severe human disease, particularly for desmin and keratins, is steadily increasing

New Methodologies to Study DNA Repair Processes in Space and Time Within Living Cells

International audienceDNA repair requires a coordinated effort from an array of factors that play different roles in the DNA damage response from recognizing and signaling the presence of a break, creating a repair competent environment, and physically repairing the lesion. Due to the rapid nature of many of these events, live-cell microscopy has become an invaluable method to study this process. In this review we outline commonly used tools to induce DNA damage under the microscope and discuss spatio-temporal analysis tools that can bring added information regarding protein dynamics at sites of damage. In particular, we show how to go beyond the classical analysis of protein recruitment curves to be able to assess the dynamic association of the repair factors with the DNA lesions as well as the target-search strategies used to efficiently find these lesions. Finally, we discuss how the use of mathematical models, combined with experimental evidence, can be used to better interpret the complex dynamics of repair proteins at DNA lesions

Three-Dimensional to Three-Dimensional Image Fusion-Guided Thoracic Endovascular Aortic Repair without Iodine Injection

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Type B Aortic Dissection Treated With a Branched Aortic Arch Stent Graft and the STABILISE Technique

We report the case of a 57-year-old woman diagnosed with an asymptomatic chronic type B aortic dissection. The maximum aortic diameter was 70 mm in the proximal descending thoracic aorta. The entry tear was located at the aortic isthmus, and the proximal neck included all of the supra-aortic trunks. The targeted proximal neck was ≥q 25 mm. The dissection extended to the infrarenal aorta. The patient was treated with a custom branched aortic graft with two branches, one for the innominate trunk and one for the left common carotid artery, combined with the stent-assisted balloon-induced intimal disruption and relamination technique. This combined technique seemed to provide a proximal seal zone in the arch and allow remodeling of the distal aorta in this patient with aneurysmal type B aortic dissection

Mathematical models converge on PGC1α as the key metabolic integrator of SIRT1 and AMPK regulation of the circadian clock

International audienceHow the mammalian circadian clock interacts with metabolism and its possible implications in metabolic diseases are actively studied. In PNAS, Foteinou et al. (1) propose a mathematical model of the circadian clock that incorporates the metabolic sensor SIRT1 and validate it with cell experiments. Their findings shed light on conflicting reports by Asher et al. (2) and Nakahata et al. (3) about the effect of SIRT1 deficiency on clock function and SIRT1 targets. The authors conclude that SIRT1 acts on the clock not only via the well-known clock protein PER2, but also through PGC-1α, a transcriptional co-activator of the BMAL1 clock gene with key metabolic functions. Interestingly, the Foteinou model is comparable to the model designed by Woller et al. (4) to understand the mechanisms of liver clock disruption observed upon high-fat diet (HFD) consumption. The two models describe the dynamics of the same molecular network, except that Woller et al. additionally consider clock regulation by the energy sensor AMPK. Remarkably, both models point to a key role of PGC-1α in the circadian clock from different perspectives. The Woller model takes into account the NAMPT-NAD+-SIRT1-PGC1α-ROR-BMAL1 metabolic loop and show its requirement to reproduce the dampened oscillations in clock gene expression observed by Hatori et al. (5) and Eckel-Mahan et al. (6) upon HFD feeding, a condition mimicked by altered AMPK activity. On the other hand, Foteinou et al. (1) report that inclusion of PGC-1α in their model is needed to reproduce correctly the altered reporter expression levels upon combined SIRT1 and BMAL1 silencing. These findings confirm the role of PGC-1α linking SIRT1 and AMPK activities: PGC-1α needs to be phosphorylated by AMPK before it can be deacetylated by SIRT1 (7). The key role of PGC-1α