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PDF file, 198K, Expression of Wnt3a in a panel of breast cancer cell lines.

PDF file, 101K, Characterization of the antibodies used in the study.

PDF file, 153K, Cocultivated human mammary adipocytes overexpress FSP-1, but not alphaSMA, and exhibit an activated phenotype.

PDF file, 74K, Age, anthropometric characteristics of control and cases series and clinical characteristics of breast cancer patients.

PDF file, 65K, Mature adipocytes dedifferentiation is not associated with changes in cell number or cell cycle distribution.

PDF file, 89K.

PDF file, 58K, Sequences and concentrations of the primers used to detect human and murine genes expression by qPCR.

Resume Le tissu adipeux est un organe central jouant de multiples roles, comme la protection thermique, le stockage energetique, la secretion d’hormones participant a l’homeostasie generale. Au cours du vieillissement, le tissu adipeux blanc (TABl) subit un remodelage quantitatif et qualitatif. En effet, il est a la fois le siege d’une redistribution geographique, de remodelages cellulaires et d’une modification de ses capacites fonctionnelles. La relocalisation du TABl sous-cutane au profit du TABl visceral et l’augmentation du stockage ectopique de lipides (foie, pancreas, muscle) s’accompagnent de la modification de son profil secretoire et de sa cellularite. A cela, s’ajoutent l’apparition de cellules senescentes au sein du tissu adipeux et la perte des capacites de renouvellement des cellules progenitrices. Ainsi, ces modifications du TABl entrainent une alteration de l’homeostasie generale et contribuent a l’insulino-resistance, a une dysfonction cardiovasculaire, a la perte de mobilite, mais egalement aux dysfonctions cognitives en participant au phenomene d’inflammation systemique generale retrouvee au cours du vieillissement. Une meilleure comprehension des effets de l’âge sur le TABl devrait permettre d’identifier de nouvelles cibles therapeutiques pour lutter contre la fragilite associee a l’âge et ameliorer la qualite de vie en ciblant cet organe central.

Background After cardiac surgery, postoperative delirium (POD) is common and is associated with long-term changes in cognitive function. Impact on health-related quality of life (QOL) and long-term dependence are not well known. This aim of this study is to evaluate the role of POD in poor evolution at three years after surgery including poor QOL and dependence and mortality. Patients and methods We enrolled and followed 173 patients 60 years of age or older who were planning to undergo cardiac surgery with cardiopulmonary bypass. The primary composite outcome was death of any causes, or patients with either a loss of QOL (evaluated with of EuroQuol verbal 5D EQ5D less than 50), or a loss of two points on the instrumental activities of daily living occurring three years after surgery. POD was diagnosed with the use of Confusion Assessment Method. Multivariate logistic regression was performed. Results At three years, 74 patients (42.8%) had a poor evolution. Independent risk factors in poor patient evolution were sex (female gender; OR: 3.6; 95%CI: 1.45-8.7; p=0.006), metabolic status (diabetic patients; OR: 4; 95%CI: 1.6-10.2; p=0.002), Euroscore 2 (Euroscore 2 >1.5; OR: 5.2; 95%CI: 1.7-15.4; p=0.003) and POD (OR: 3.3; 95%CI 1.4-7.8; p=0.006). Coronary disease was protective (OR: 0.3; 95%CI: 0.14-0.71; p=0.006). Conclusion After cardiac surgery, POD significantly altered patient evolution and increased risk of dependence and loss of QOL.

Dysregulations of lipid metabolism in the liver may trigger steatosis progression, leading to potentially severe clinical consequences such as nonalcoholic fatty liver diseases (NAFLDs). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis. Mice with liver-specific Hmgb1 deficiency display exacerbated liver steatosis, while Hmgb1-overexpressing mice exhibited a protection from fatty liver progression when subjected to nutritional stress. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXRα and PPARγ activity. HMGB1 repression is not mediated through nucleosome landscape reorganization but rather via a preferential DNA occupation in a region carrying genes regulated by LXRα and PPARγ. Together, these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target the LXRα-PPARγ axis during NAFLD. Published version This study was supported by grants from INSERM, Paul Sabatier University, the Agence Nationale de la Recherche (ANR-17-CE14-0016, to J.-P.P.), and the Région Occitanie and Association Française d’Etude et de Recherche sur l’Obésité (to J.-P.P.). J.P. was supported by a scholarship from Paul Sabatier University. E.P. was supported by a scholarship from Agence Nationale de la Recherche (ANR-17-CE14-0016). R.P. was supported by a scholarship from Région Midi-Pyrénées-INSERM (no. 15050341). O.B.-S. and L.C.-S. and the proteomic facility were supported, in part, by the Région Occitanie, European funds (Fonds Européens de Développement Régional, FEDER), Toulouse Métropole, and the French Ministry of Research with the Investissement d’Avenir Infrastructures Nationales en Biologie et Santé program (ProFI, Proteomics French Infrastructure project, ANR-10-INBS-08).

International audience; Aging is the most important risk factor for the onset of several chronic diseases and functional decline. Understanding the interplays between biological aging and the biology of diseases and functional loss as well as integrating a function-centered approach to the care pathway of older adults are crucial steps towards the elaboration of preventive strategies (both pharmacological and non-pharmacological) against the onset and severity of burdensome chronic conditions during aging. In order to tackle these two crucial challenges, ie, how both the manipulation of biological aging and the implementation of a function-centered care pathway (the Integrated Care for Older People (ICOPE) model of the World Health Organization) may contribute to the trajectories of healthy aging, a new initiative on Gerosciences was built: the INSPIRE research program. The present article describes the scientific background on which the foundations of the INSPIRE program have been constructed and provides the general lines of this initiative that involves researchers from basic and translational science, clinical gerontology, geriatrics and primary care, and public health.

Numerous recent studies have shown that in the continuum of cardiovascular diseases, the measurement of arterial stiffness has powerful predictive value in cardiovascular risk and mortality and that this value is independent of other conventional risk factors, such as age, cholesterol levels, diabetes, smoking, or average blood pressure. Vascular stiffening is often the main cause of arterial hypertension (AHT), which is common in the presence of obesity. However, the mechanisms leading to vascular stiffening, as well as preventive factors, remain unclear. The aim of the present study was to investigate the consequences of apelin deficiency on the vascular stiffening and wall remodeling of aorta in mice. This factor freed by visceral adipose tissue, is known for its homeostasic role in lipid and vascular metabolisms, or again in inflammation. We compared the level of metabolic markers, inflammation of white adipose tissue (WAT), and aortic wall remodeling from functional and structural approaches in apelin-deficient and wild-type (WT) mice. Apelin-deficient mice were generated by knockout of the apelin gene (APL-KO). From 8 mice by groups, aortic stiffness was analyzed by pulse wave velocity measurements and by characterizations of collagen and elastic fibers. Mann–Whitney statistical test determined the significant data (p

International audience; The number of older obese adults is increasing worldwide. Whether obese adults show similar health benefits in response to lifestyle interventions at different ages is unknown. The study enrolled 25 obese men (body mass index: 31-39 kg/m2) in two arms according to age (30-40 and 60-70 yr old). Participants underwent an 8-wk intervention with moderate calorie restriction (∼20% below individual energy requirements) and supervised endurance training resulting in ∼5% weight loss. Body composition was measured using dual energy X-ray absorptiometry. Insulin sensitivity was assessed during a hypersinsulinemic-euglycemic clamp. Cardiometabolic profile was derived from blood parameters. Subcutaneous fat and vastus lateralis muscle biopsies were used for ex vivo analyses. Two-way repeated-measure ANOVA and linear mixed models were used to evaluate the response to lifestyle intervention and comparison between the two groups. Fat mass was decreased and bone mass was preserved in the two groups after intervention. Muscle mass decreased significantly in older obese men. Cardiovascular risk (Framingham risk score, plasma triglyceride, and cholesterol) and insulin sensitivity were greatly improved to a similar extent in the two age groups after intervention. Changes in adipose tissue and skeletal muscle transcriptomes were marginal. Analysis of the differential response to the lifestyle intervention showed tenuous differences between age groups. These data suggest that lifestyle intervention combining calorie restriction and exercise shows similar beneficial effects on cardiometabolic risk and insulin sensitivity in younger and older obese men. However, attention must be paid to potential loss of muscle mass in response to weight loss in older obese men.NEW & NOTEWORTHY Rise in obesity and aging worldwide are major trends of critical importance in public health. This study addresses a current challenge in obesity management. Do older obese adults respond differently to a lifestyle intervention composed of moderate calorie restriction and supervised physical activity than younger ones? The main conclusion of the study is that older and younger obese men similarly benefit from the intervention in terms of cardiometabolic risk.

Insulin resistance is a key event in type 2 diabetes onset and a major comorbidity of obesity. It results from a combination of fat excess-triggered defects, including lipotoxicity and metaflammation, but the causal mechanisms remain difficult to identify. Here, we report that hyperactivation of the tyrosine phosphatase SHP2 found in Noonan syndrome (NS) led to an unsuspected insulin resistance profile uncoupled from altered lipid management (for example, obesity or ectopic lipid deposits) in both patients and mice. Functional exploration of an NS mouse model revealed this insulin resistance phenotype correlated with constitutive inflammation of tissues involved in the regulation of glucose metabolism. Bone marrow transplantation and macrophage depletion improved glucose homeostasis and decreased metaflammation in the mice, highlighting a key role of macrophages. In-depth analysis of bone marrow-derived macrophages in vitro and liver macrophages showed that hyperactive SHP2 promoted a proinflammatory phenotype, modified resident macrophage homeostasis, and triggered monocyte infiltration. Consistent with a role of SHP2 in promoting inflammation-driven insulin resistance, pharmaceutical SHP2 inhibition in obese diabetic mice improved insulin sensitivity even better than conventional antidiabetic molecules by specifically reducing metaflammation and alleviating macrophage activation. Together, these results reveal that SHP2 hyperactivation leads to inflammation-triggered metabolic impairments and highlight the therapeutical potential of SHP2 inhibition to ameliorate insulin resistance.

Dysregulations of lipid metabolism in the liver may trigger steatosis progression leading to potentially severe clinical consequences such as non-alcoholic fatty liver diseases (NAFLD). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and the activity of multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis during metabolic stress in NAFLD. Mice with liver-specific Hmgb1-deficiency display exacerbated liver steatosis and hepatic insulin resistance when subjected to a high-fat diet or after fasting/refeeding. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXRα activity resulting in increased lipogenesis. HMGB1 repression is not mediated through nucleosome landscape re-organization but rather via a preferential DNA occupation in region carrying genes regulated by LXRα. Together these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target LXRα axis during NAFLD.

Vascular stiffness is often the main cause of arterial hypertension and its complications including atherosclerosis, observed during obesity. However, the mechanisms leading to this rigidity or the preventing factors are misknown. We hypothesized that apelin, known for its beneficial effects on lipid, inflammatory, and vascular metabolism, could be a protective factor against vascular stiffness. We used mice deficient for the apelin gene (KO-APL) and compared with wild-type mice (WT) at the level of metabolic markers and inflammations of white adipose tissue (WAT), as well as aortic functional and anatomical parameters. KO-APL mice developed an inflammation associated with significant remodeling of WAT, in particular with the protease expressions such as neutrophil elastase or cathepsin S. From a vascular point of view, these same elastases are involved in the fragmentation of elastic fibers, explaining the increase in vascular velocity of pulse wave and arterial hypertension. Interestingly, univariate correlation analysis showed that the inflammation markers and protease expression of WAT were associated with remodeling of the vascular wall. Our results suggest that the modifications induced by the absence of apelin particularly in WAT, could facilitate the expression of elastases and the rupture of elastic fibers, necessary to maintain elastance. This discovery is fundamental because the synthesis of elastic fibers stops as of adolescence and is not renewed during the entire life of human. The preservation of these fibers is therefore critical in maintaining vascular homeostasis. Thus, Apelin could be an interesting therapeutic route to protect the premature wear of elastic fibers.

Apelin, a peptide with several active isoforms ranging from 36 to 12 amino acids and its receptor APJ, a G-protein-coupled receptor, are widely distributed. However, apelin has emerged as an adipokine more than fifteen years ago, integrating the field of inter-organs interactions. The apelin/APJ system plays important roles in several physiological functions both in rodent and humans such as fluid homeostasis, cardiovascular physiology, angiogenesis, energy metabolism. Thus the apelin/APJ system has generated great interest as a potential therapeutic target in different pathologies. The present review will consider the effects of apelin in metabolic diseases such as obesity and diabetes with a focus on diabetic cardiomyopathy among the complications associated with diabetes and APJ agonists or antagonists of interest in these diseases.

International audience; Background : The Geroscience field focuses on the core biological mechanisms of aging, which are involved in the onset of age-related diseases, as well as declines in intrinsic capacity (IC) (body functions) leading to dependency. A better understanding on how to measure the true age of an individual or biological aging is an essential step that may lead to the definition of putative markers capable of predicting healthy aging. Objectives : The main objective of the INStitute for Prevention healthy aging and medicine Rejuvenative (INSPIRE) Platform initiative is to build a program for Geroscience and healthy aging research going from animal models to humans and the health care system. The specific aim of the INSPIRE human translational cohort (INSPIRE-T cohort) is to gather clinical, digital and imaging data, and perform relevant and extensive biobanking to allow basic and translational research on humans.Methods : The INSPIRE-T cohort consists in a population study comprising 1000 individuals in Toulouse and surrounding areas (France) of different ages (20 years or over - no upper limit for age) and functional capacity levels (from robustness to frailty, and even dependency) with follow-up over 10 years. Diversified data are collected annually in research facilities or at home according to standardized procedures. Between two annual visits, IC domains are monitored every 4-month by using the ICOPE Monitor app developed in collaboration with WHO. Once IC decline is confirmed, participants will have a clinical assessment and blood sampling to investigate markers of aging at the time IC declines are detected. Biospecimens include blood, urine, saliva, and dental plaque that are collected from all subjects at baseline and then, annually. Nasopharyngeal swabs and cutaneous surface samples are collected in a large subgroup of subjects every two years. Feces, hair bulb and skin biopsy are collected optionally at the baseline visit and will be performed again during the longitudinal follow up.Expected Results : Recruitment started on October 2019 and is expected to last for two years. Bio-resources collected and explored in the INSPIRE-T cohort will be available for academic and industry partners aiming to identify robust (set of) markers of aging, age-related diseases and IC evolution that could be pharmacologically or non-pharmacologically targetable. The INSPIRE-T will also aim to develop an integrative approach to explore the use of innovative technologies and a new, function and person-centered health care pathway that will promote a healthy aging.Electronic Supplementary Material.Supplementary material : is available for this article at 10.14283/jfa.2020.38 and is accessible for authorized users.

Background Liposomal bupivacaine (Exparel®) is a sustained-release formulation of bupivacaine for use in surgical infiltration anaesthesia. We analysed the histological nerve toxicity and clinical effectiveness of perineural Exparel® alone or with added dexamethasone in a mouse model. Methods We assigned 98 mice receiving a perineural sciatic nerve injection into seven groups: sham (n=14, perineural saline), B (n=14, perineural bupivacaine), BDIP (n=14, perineural bupivacaine + intraperitoneal dexamethasone), BDPN (n=14, perineural bupivacaine + perineural dexamethasone), E (n=14, perineural Exparel®), EDIP (n=14, perineural Exparel® + intraperitoneal dexamethasone), and EDPN (n=14, perineural Exparel® + perineural dexamethasone). The duration of thermoalgesic and motor block was evaluated in 49 mice (seven mice randomly selected by group) every 30 min until recovery. Mice were killed for sciatic nerve histological assessment at 14 or 28 days. Results The median duration of motor block was 90, 120, 120, 120, 180, and 180 min and the duration of thermoalgesic block was 240, 300, 360, 360, 360, and 420 min for groups B, BDIP, BDPN, E, EDIP, and EDPN, respectively. The B group mice showed mild neural inflammation at 14 days and the E group mice showed mild neural inflammation at 28 days. Addition (intraperitoneal or perineural) of dexamethasone reduced neural inflammation induced by bupivacaine, whereas only perineural dexamethasone reduced neural inflammation induced by Exparel®. Conclusions Perineural or systemic dexamethasone had a protective effect against the neural inflammation induced by bupivacaine, and perineural dexamethasone attenuated delayed inflammation induced by perineural Exparel®.

International audience; The Geroscience aims at a better understanding of the biological processes of aging, to prevent and/or delay the onset of chronic diseases and disability as well as to reduce the severity of these adverse clinical outcomes. Geroscience thus open up new perspectives of care to live a healthy aging, that is to say without dependency. To date, life expectancy in healthy aging is not increasing as fast as lifespan. The identification of biomarkers of aging is critical to predict adverse outcomes during aging, to implement interventions to reduce them, and to monitor the response to these interventions. In this narrative review, we gathered information about biomarkers of aging under the perspective of Geroscience. Based on the current literature, for each hallmark of biological aging, we proposed a putative biomarker of healthy aging, chosen for their association with mortality, age-related chronic diseases, frailty and/or functional loss. We also discussed how they could be validated as useful predictive biomarkers.

The International Conference of Frailty and Sarcopenia Research was held in Miami, Florida, in February of 2019 (1). The 9th edition of this conference had the highest attendance rate since its debut and is now a major venue that attracts the best key opinion leaders in the field of sarcopenia and frailty. Approximately 400- 500 delegates from around the world shared their results across the spectrum of research, from animal studies targeting novel mechanisms to large clinical trials for improving function, reducing disability, and improving quality of life in aging persons. With the recent implementation of ICD-10 code for sarcopenia (2), more and more industry leaders are looking for novel strategies and treatments counteracting the decline of skeletal muscle and physical function. By identifying sarcopenia as a disease (2) and the increasing number of older adults in the world (3), targeting and understanding the process of sarcopenia will be essential for geriatricians and gerontologists in the coming years. This paper will present the major highlights of this conference.

We describe here a collective and experimental research project-based learning (ERPBL) for master’s students that can be used to illustrate some basic concepts on glucose/lipid homeostasis and renal function around a topical issue. The primary objective of this ERPBL was to strengthen students’ knowledge and understanding of physiology and pathophysiology. The secondary objectives were to help students to develop technical/practical abilities and acquire transversal skills with real-world connections. Obesity is a worldwide public health problem that increases the risk for developing type 2 diabetes and nephropathies. To study the impact of western dietary habits, students evaluated the effects of a diet enriched with fat and cola [high-fat and cola diet (HFCD)] on metabolism and renal function in mice. Students mainly worked in tandem to prepare and perform experiments, but also collectively to compile, analyze, and discuss data. Students showed that HFCD-fed mice 1) developed obesity; 2) exhibited glucose homeostasis impairments associated to ectopic fat storage; and 3) displayed reduced glomerular filtration. The educational benefit of the program was estimated using three evaluation metrics: a conventional multicriteria assessment by teachers, a pre-/posttest, and a self-evaluation questionnaire. They showed that the current approach successfully strengthened scientific student knowledge and understanding of physiology/pathophysiology. In addition, it helped students develop new skills, such as technical and transversal skills. We concluded that this ERPBL dealing with the pathophysiology of obesity was strongly beneficial for master’s students, thereby appearing as an efficient and performing educational tool.

Mammalian aging is often characterized by metabolic disturbances, cognitive declines and DNA repairs deficiency, but the underlying molecular mechanisms are still not well understood. Alterations in DNA repair can significantly exacerbate aging. Mammalian neuronal cells which accumulate unrepaired DNA damage over time could potentially lead to brain functions disorders. Focusing on the ATP-dependent RecQ-type DNA helicase, an enzyme involved in repair of double strand DNA, a mouse model of Werner syndrome (WS) had been proposed as a model of accelerated aging. Until now, no study has investigated the impact of this premature aging syndrome on learning and memory. Spatial memory and cognitive flexibility are particularly affected by the aging process in both men and rodents. Studies have shown that aged mice exhibited similar performance than young adult mice on non-hippocampus dependent memory whereas their performances were decreased in hippocampus-dependent tasks. In this study, we have submitted 3, 5 and 8 month-old WS mice to several behavioral paradigms to evaluate hippocampus-dependent (spatial object location, Morris water maze and fear conditioning) and non hippocampus-dependent (object recognition) memories. No effect on the locomotion activity and anxiety level has been observed in adult WS mice. Interestingly, the 8 month-old WS mice exhibit long-term memory impairment similar to aged mice, suggesting that adult WS mice do develop some aspects of cognitive aging.

International audience; Kidney function is altered by age together with a declined filtration capacity of 5-10% per decade after 35 years. Renal aging shares many characteristics with chronic kidney disease. Plasma levels of the bioactive peptide apelin also decline with age and apelin has been shown to be protective in chronic kidney disease. Therefore we evaluated whether apelin could also improve aging-induced renal lesions and function in mice. Since urine is for the major part composed of proteins and peptides originating from the kidney, we first studied apelin-induced changes, in the aging urinary peptidome. Despite the recently published age-associated plasma decrease of apelin, expression of the peptide and its receptor was increased in the kidneys of 24 months old mice. Twenty-eight days treatment with apelin significantly modified the urinary peptidome of 3 and 24 months old mice towards a signature suggesting more advanced age at 3 months, and a younger age at 24 months. The latter was accompanied by a decreased staining of collagen (Sirius red staining) in 24 months old apelin-treated mice, without changing aging-induced glomerular hypertrophy. In addition, apelin was without effect on aging-induced renal autophagy, apoptosis, inflammation and reduced renal function. In conclusion, treatment of aged mice with apelin had a limited effect on kidney lesions although modifying the urinary peptidome towards a younger signature. This supports evidence of apelin inducing more general beneficial effects on other aging organs, muscles in particular, as recently shown for sarcopenia, markers of which end up via the glomerular filtration in urine.

Objective To demonstrate that glycemia and insulin resistance are controlled by a mechanism involving the adaptive immune system and gut microbiota crosstalk. Methods We triggered the immune system with microbial extracts specifically from the intestinal ileum contents of HFD-diabetic mice by the process of immunization. 35 days later, immunized mice were fed a HFD for up to two months in order to challenge the development of metabolic features. The immune responses were quantified. Eventually, adoptive transfer of immune cells from the microbiota-immunized mice to naïve mice was performed to demonstrate the causality of the microbiota-stimulated adaptive immune system on the development of metabolic disease. The gut microbiota of the immunized HFD-fed mice was characterized in order to demonstrate whether the manipulation of the microbiota to immune system interaction reverses the causal deleterious effect of gut microbiota dysbiosis on metabolic disease. Results Subcutaneous injection (immunization procedure) of ileum microbial extracts prevented hyperglycemia and insulin resistance in a dose-dependent manner in response to a HFD. The immunization enhanced the proliferation of CD4 and CD8 T cells in lymphoid organs, also increased cytokine production and antibody secretion. As a mechanism explaining the metabolic improvement, the immunization procedure reversed gut microbiota dysbiosis. Finally, adoptive transfer of immune cells from immunized mice improved metabolic features in response to HFD. Conclusions Glycemia and insulin sensitivity can be regulated by triggering the adaptive immunity to microbiota interaction. This reduces the gut microbiota dysbiosis induced by a fat-enriched diet., Highlights • Triggering adaptive immune response with ileum bacteria extracts prevents HFD-induced metabolic disease. • Triggering adaptive immune response with ileum bacteria extracts improves gut microbiota dysbiosis. • Triggering adaptive immune response with ileum bacteria extract regulates the intestinal immune system. • First microbiota based vaccination strategy of metabolic disease.

Sarcopenia, the degenerative loss of skeletal muscle mass, quality and strength, lacks early diagnostic tools and new therapeutic strategies to prevent the frailty-to-disability transition often responsible for the medical institutionalization of elderly individuals. Herein we report that production of the endogenous peptide apelin, induced by muscle contraction, is reduced in an age-dependent manner in humans and rodents and is positively associated with the beneficial effects of exercise in older persons. Mice deficient in either apelin or its receptor (APLNR) presented dramatic alterations in muscle function with increasing age. Various strategies that restored apelin signaling during aging further demonstrated that this peptide considerably enhanced muscle function by triggering mitochondriogenesis, autophagy and anti-inflammatory pathways in myofibers as well as enhancing the regenerative capacity by targeting muscle stem cells. Taken together, these findings revealed positive regulatory feedback between physical activity, apelin and muscle function and identified apelin both as a tool for diagnosis of early sarcopenia and as the target of an innovative pharmacological strategy to prevent age-associated muscle weakness and restore physical autonomy.

Le gène codant pour le récepteur de l’apeline (APJ) a été cloné dès 1993, et son ligand identifié en 1998. L’expression du récepteur APJ au niveau du système nerveux central, notamment dans l’hypothalamus, ainsi que dans divers tissus (cœur, vaisseaux, estomac, etc.), en fait une cible pharmacologique de choix. En effet, les recherches sur APJ ont permis le développement de molécules essentiellement peptidiques permettant d’activer et/ou de bloquer le récepteur et, plus récemment, de découvrir un autre ligand endogène : apela. Parmi les fonctions régulées par le système APJ/apeline, le contrôle du métabolisme énergétique apparaît aujourd’hui au tout premier plan. Une meilleure connaissance de la pharmacologie du récepteur APJ devrait donc permettre d’envisager une approche thérapeutique innovante dans la lutte contre les maladies métaboliques.

The mechanisms underlying the relationships between nutritional status and immunity remain to be fully characterized. The present study was undertaken to analyze by flow cytometry, in the context of diet-induced obesity, the status of immune cells in subcutaneous, and epididymal fat depots in wild-type and immunodeficient Rag2-/- mice submitted to nutritional challenge, i.e., 48-h fasting and 1-week refeeding. In parallel, the responsiveness of mature adipocytes and immune cells in bone marrow, lymph node, and liver were also analyzed. The results show that fasting in obese wild-type mice induces a prominent lipolysis in epididymal AT and immunosuppression restricted to both subcutaneous and epididymal AT, characterized by reduced number of CD4+ T and B lymphocytes and M1/M2 macrophages associated with reduced leptin and increased FGF21 expression in mature adipocytes. One-week refeeding was sufficient to reverse the fasting-induced effects. Obese immunodeficient mice under nutritional challenge exhibited no changes in adipocyte leptin expression and no marked trafficking of AT macrophages or NK cells, while the fasted-induced upregulation of FGF21 expression was maintained as well as the lipolytic responses. The present results demonstrate that, in a context of diet-induced obesity, fasting-induced immunosuppression is restricted to fat depots in immunocompetent mice. Lack of adipocyte leptin regulation and fasting-induced immunosuppression in obese immunodeficient mice strongly suggests that lymphocytes are involved in the modulation of adipocyte leptin expression on one hand and on the other that leptin is involved in the immune changes in AT according to nutritional status.

To fight against metabolic disorders such as insulin resistance, new alimentary behaviors are developed. For instance, hyperproteined, gluten-free, or collagen-enriched diets could be preconized in order to reduce the consequences of obesity. In this aim, this study evaluates the potential effects of warm sea fish collagen peptides (Naticol®) on representative metabolic and inflammatory parameters. For that, male C57Bl6/J mice fed with either a chow- (CD) or high-fat diet (HFD) were submitted or not to specific collagen peptides in drinking water (4 g/kg bw/d) for 20 weeks. Weight, body composition, glucose tolerance, and insulin sensitivity were followed up. Effects of fish collagen peptides on various blood parameters reflecting the metabolism status were also measured (free fatty acids, triglycerides, cholesterol, hormones) together with adipocyte inflammation. Results showed that HFD-fed mice supplemented by fish collagen peptides exhibited a significant lower increase in body weight as soon as the twelfth week of treatment whereas no effect of the peptide was observed in CD fed mice. In line with this result, a weaker increase in fat mass in HFD-fed mice supplemented with Naticol® at both 9 and 18 weeks of treatment was also observed. In spite of this resistance to obesity promoted by fish collagen peptides treatment, no difference in glucose tolerance was found between groups whereas mice treated with Naticol® exhibited a lower basal glycemia. Also, even if no effect of the treatment on adipocyte lipolysis was found, a decrease of inflammatory cytokines was retrieved in collagen-supplemented group arguing for a potential better insulin sensitivity. Altogether, these results need to be completed but are the first describing a benefic role of warm sea fish collagen peptides in a context of metabolic disease paving the route for a potential utilization in human obesity-associated disorders.

Objectives Screening for sarcopenia in daily practice can be challenging. Our objective was to explore whether the SARC-F questionnaire is a valid screening tool for sarcopenia (defined by the Foundation for the National Institutes of Health [FNIH] criteria). Moreover, we evaluated the physical performance of older women according to the SARC-F questionnaire. Design Cross-sectional study. Participants Data from the Toulouse and Lyon EPIDemiologie de l’OSteoporose study (EPIDOS) on 3025 women living in the community (mean age: 80.5 ± 3.9 years), without a previous history of hip fracture, were assessed. Measurements The SARC-F self-report questionnaire score ranges from 0 to 10: a score ≥4 defines sarcopenia. The FNIH criteria uses handgrip strength (GS) and appendicular lean mass (ALM; assessed by DXA) divided by body mass index (BMI) to define sarcopenia. Outcome measures were the following performance-based tests: knee-extension strength, 6-m gait speed, and a repeated chair-stand test. The associations of sarcopenia with performance-based tests was examined using bootstrap multiple linear-regression models; adjusted R2 determined the percentage variation for each outcome explained by the model. Results Prevalence of sarcopenia was 16.7% (n = 504) according to the SARC-F questionnaire and 1.8% (n = 49) using the FNIH criteria. Sensibility and specificity of the SARC-F to diagnose sarcopenia (defined by FNIH criteria) were 34% and 85%, respectively. Sarcopenic women defined by SARC-F had significantly lower physical performance than nonsarcopenic women. The SARC-F improved the ability to predict poor physical performance. Conclusion The validity of the SARC-F questionnaire to screen for sarcopenia, when compared with the FNIH criteria, was limited. However, sarcopenia defined by the SARC-F questionnaire substantially improved the predictive value of clinical characteristics of patients to predict poor physical performance.

Aims Apelin is a recently identified adipokine known to improve glucose tolerance and insulin sensitivity in murine models. This study was dedicated to the proof of concept that apelin administration also enhances insulin sensitivity in humans. Materials and methods Healthy overweight men were enrolled in this randomized, double-blind, placebo-controlled, cross-over study that successively considered the efficacy and the tolerance of two doses of (pyr1)-Apelin-13. A first group of subjects received 9 nmol/kg (n=8) of (pyr1)-Apelin-13 and, after examination of safety data, a second group received 30 nmol/kg (n=8). Each volunteer underwent two hyperinsulinemic-euglycemic clamps where the basal level of glucose infusion rate (GIR) was measured from the 90th to the 120th minutes (level 1). Apelin or placebo continuous i.v. administration was then started for 2 hours and GIR was finally evaluated from the 210th to the 240th minutes (level 2). Primary evaluation endpoint was the difference in GIR between level 2 and level 1 (ΔGIR). Results A slight increase in ΔGIR was observed with the low apelin dose (+0.65 ± 0.71 mg/kg/min, p=0.055) whereas the highest dose significantly improved insulin sensitivity (+0.82 ± 0.71 mg/kg/min, p=0.033). Cardiovascular monitoring and safety reports did not reveal any side effect of apelin administration. Conclusion As the first demonstration of the insulin sensitizing action of apelin in humans alongside numerous rodent studies, this trial confirms that the apelin/APJ pathway should be considered as a new target to design alternative therapeutic strategies to control insulin resistance in type 2 diabetic patients.

Ageing is a complex process characterised by a systemic and progressive deterioration of biological functions. As ageing is associated with an increased prevalence of age-related chronic disorders, understanding its underlying molecular mechanisms can pave the way for therapeutic interventions and managing complications. Animal models such as mice are commonly used in ageing research as they have a shorter lifespan in comparison to humans and are also genetically close to humans. To assess the translatability of mouse ageing to human ageing, the urinary proteome in 89 wild-type (C57BL/6) mice aged between 8-96 weeks was investigated using capillary electrophoresis coupled to mass spectrometry (CE-MS). Using age as a continuous variable, 295 peptides significantly correlated with age in mice were identified. To investigate the relevance of using mouse models in human ageing studies, a comparison was performed with a previous correlation analysis using 1227 healthy subjects. In mice and humans, a decrease in urinary excretion of fibrillar collagens and an increase of uromodulin fragments was observed with advanced age. Of the 295 peptides correlating with age, 49 had a strong homology to the respective human age-related peptides. These ortholog peptides including several collagen (N = 44) and uromodulin (N = 5) fragments were used to generate an ageing classifier that was able to discriminate the age among both wild-type mice and healthy subjects. Additionally, the ageing classifier depicted that telomerase knock-out mice were older than their chronological age. Hence, with a focus on ortholog urinary peptides mouse ageing can be translated to human ageing.

International audience; BACKGROUND & AIMS: Glucose is absorbed into intestine cells via the sodium glucose transporter 1 (SGLT-1) and glucose transporter 2 (GLUT2); various peptides and hormones control this process. Apelin is a peptide that regulates glucose homeostasis and is produced by proximal digestive cells; we studied whether glucose modulates apelin secretion by enterocytes and the effects of apelin on intestinal glucose absorption. METHODS: We characterized glucose-related luminal apelin secretion in vivo and ex vivo by mass spectroscopy and immunologic techniques. The effects of apelin on (14)C-labeled glucose transport were determined in jejunal loops and in mice following apelin gavage. We determined levels of GLUT2 and SGLT-1 proteins and phosphorylation of AMPKα2 by immunoblotting. The net effect of apelin on intestinal glucose transepithelial transport was determined in mice. RESULTS: Glucose stimulated luminal secretion of the pyroglutaminated apelin-13 isoform ([Pyr-1]-apelin-13) in the small intestine of mice. Apelin increased specific glucose flux through the gastric epithelial barrier in jejunal loops and in vivo following oral glucose administration. Conversely, pharmacologic apelin blockade in the intestine reduced the increased glycemia that occurs following oral glucose administration. Apelin activity was associated with phosphorylation of AMPKα2 and a rapid increase of the GLUT2/SGLT-1 protein ratio in the brush border membrane. CONCLUSIONS: Glucose amplifies its own transport from the intestinal lumen to the bloodstream by increasing luminal apelin secretion. In the lumen, active apelin regulates carbohydrate flux through enterocytes by promoting AMPKα2 phosphorylation and modifying the ratio of SGLT-1:GLUT2. The glucose-apelin cycle might be pharmacologically handled to regulate glucose absorption and assess better control of glucose homeostasis.

Tous les éléments référencés sont disponibles au téléchargement à l’adresse suivante : https://github.com/WilliamR03/Dissimilarity-dataset-characterization.gi; National audience; La caractérisation de jeu de données reste un verrou majeur de l'analyse de données intelligente. Une majorité d'approches à ce problème agrègent les informations décrivant les attributs individuels des jeux de données, ce qui représente une perte d'information. Nous proposons une approche par dissimilarité permettant d'éviter cette agrégation, et étudions son intérêt dans la caractérisation des performances d'algorithmes de classification et dans la résolution de problèmes de méta-apprentissage.

International audience; Insulin resistance is a main feature of obesity and type 2 diabetes mellitus (T2DM). Several mechanisms linking obesity to insulin resistance have been proposed. Adipose tissue modulates metabolism by secreting a variety of factors, which exhibit altered production during obesity. Apelin, a small peptide present in a number of tissues and also produced and secreted by adipocytes, has emerged as a new player with potent functions in energy metabolism, and in insulin sensitivity improvement. In this review, we describe the various metabolic functions that are affected by apelin and we present an integrated overview of recent findings that collectively propose apelin as a promising target for the treatment of T2DM.

Ataxia Telangiectasia (AT) is an autosomal recessive disorder characterized by a wide variety of progressive clinical symptoms. This includes neuronal degeneration, oculocutaneous telangiectasias, diabetes mellitus, immunodeficiency, increased risk of cancer and sensitivity to ionizing radiation. The gene mutated in this disease, ATM (Ataxia Telangiectasia Mutated), encodes a protein kinase involved in DNA double strand breaks signalling and repair. ATM deficient cells also display an increase in oxidative stress, by poorly characterized mechanism(s), which clearly contributes to the neurodegenerative aspect of the disease. Despite these advances, the occurrence of the vascular abnormalities, glucose intolerance and insulin resistance remains poorly understood. In different cellular models where ATM expression was disrupted, we demonstrated that the absence of ATM leads to an increased expression of both subunits of the transcription factor Hypoxia Inducible Factor 1 (HIF-1). We also observed enhanced trans-activating functions of HIF-1. HIF-1 is the central regulator of responses to hypoxia which induces the transcription of genes involved in angiogenesis (e.g., VEGF-Vascular Endothelial Growth Factor) and cellular metabolism (e.g., GLUT-1). Interestingly, we demonstrated that ATM disruption positively regulates both expression and function of the basal glucose transporter GLUT-1 as well as the proangiogenic factor, VEGF. In addition, our results suggest that the absence of ATM increases HIF-1 proteins biosynthesis, and this effect is dependant on the oxidative stress existing in ATM deficient cells. Our compelling results highlight a new link between ATM deficiency and the clinical features of the disease and provide a molecular link between ATM downregulation and the increase in tumor angiogenesis observed in human breast cancers.

L’apeline est un peptide dont les formes les plus biologiquement actives sont de 13, 17 ou 36 acides amines. L’apeline et son recepteur membranaire APJ sont exprimes au niveau du systeme nerveux central, notamment dans l’hypothalamus, et en peripherie surtout dans le cœur, le tissu adipeux, les cellules endotheliales des vaisseaux sanguins et le muscle squelettique. L’apeline est impliquee dans la regulation de la prise hydrique, alimentaire, les phenomenes d’angiogenese et de proliferation cellulaire. Le systeme apeline/APJ est egalement un regulateur important de l’homeostasie cardiovasculaire. Ainsi, l’apeline induit une vasodilatation dependante du NO et augmente la contraction cardiaque. Dans differentes pathologies cardiaques, une diminution de l’expression et de l’activite du systeme apeline/APJ est observee mais l’apport exogene d’apeline produit une nette amelioration faisant de ce systeme une cible privilegiee. Recemment, des effets de l’apeline sur le metabolisme energetique ont ete mis en evidence. Des resultats obtenus dans notre equipe montrent qu’in vivo, chez la souris, une injection intraveineuse d’apeline diminue la glycemie et augmente l’utilisation du glucose dans les muscles squelettiques et le tissu adipeux. L’activation du transport du glucose par l’apeline dans le muscle implique une voie en partie independante de celle de l’insuline avec activation de l’AMP-activated protein kinase et de la NO-synthase endotheliale. Ainsi, l’apeline participe au controle de l’homeostasie glucidique. De facon tres interessante, ces effets perdurent chez des souris insulinoresistantes. Le cœur est aussi le siege d’une activite metabolique importante. Au cours du diabete, des alterations metaboliques sont observees. Le systeme apeline/APJ etant fortement exprime au niveau du cœur, les effets de l’apeline sur le metabolisme energetique ouvrent des perspectives interessantes.

International audience; Adipose tissue is an active endocrine organ that produces a variety of secretory factors involved in the initiation of angiogenic processes. The bioactive peptide apelin is the endogenous ligand of the G protein-coupled receptor, APJ. Here we investigated the potential role of apelin and its receptor, APJ, in the angiogenic responses of human endothelial cells and the development of a functional vascular network in a model of adipose tissue development in mice. Treatment of human umbilical vein endothelial cells with apelin dose-dependently increased angiogenic responses, including endothelial cell migration, proliferation, and Matrigel(R) capillary tubelike structure formation. These endothelial effects of apelin were due to activation of APJ, because siRNA directed against APJ, which led to long-lasting down-regulation of APJ mRNA, abolished cell migration induced by apelin in contrast to control nonsilencing siRNA. Hypoxia up-regulated the expression of apelin in 3T3F442A adipocytes, and we therefore determined whether apelin could play a role in adipose tissue angiogenesis in vivo. Epididymal white adipose tissue (EWAT) transplantation was performed as a model of adipose tissue angiogenesis. Transplantation led to increased apelin mRNA levels 2 and 5 days after transplantation associated with tissue hypoxia, as evidenced by hydroxyprobe staining on tissue sections. Graft revascularization evolved in parallel, as the first functional vessels in EWAT grafts were observed 2 days after transplantation and a strong angiogenic response was apparent on day 14. This was confirmed by determination of graft hemoglobin levels, which are indicative of functional vascularization and were strongly increased 5 and 14 days after transplantation. The role of apelin in the graft neovascularization was then assessed by local delivery of stable complex apelin-targeting siRNA leading to dramatically reduced apelin mRNA levels and vascularization (quantified by hemogloblin content) in grafted EWAT on day 5 when compared with control siRNA. Taken together, our data provide the first evidence that apelin/APJ signaling pathways play a critical role in the development of the functional vascular network in adipose tissue. In addition, we have shown that adipocyte-derived apelin can be up-regulated by hypoxia. These findings provide novel insights into the complex relationship between adipose tissue and endothelial vascular function and may lead to new therapeutic strategies to modulate angiogenesis.