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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).

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

Apelin is a small peptide secreted by the adipose tissue notably in conditions of obesity-induced hyper-insulinemia. Apelin exerts a range of physiological functions at the periphery including the improvement of insulin sensitivity and the increase of muscle strength or cardiac contractibility. Interestingly, the brain is endowed with a high density of APJ, the single target of apelin, and growing evidence suggests various central actions of this adipokine. Recent studies reported that the intracerebroventricular infusion of apelin modulates emotional states in middle age stressed animals. However, results are so far been mixed and have not allowed for definitive conclusions about the impact of apelin on anxio-depressive-like phenotype. This study aims 1) to evaluate whether serum apelin levels are associated with mood in older adults and 2) to determine the impact of the genetic apelin inactivation in 12-month old mice fed a standard diet (STD) or in 6-month old mice fed a high fat diet (HFD). A higher plasma apelin level was associated with higher depressive symptoms in older adults. In line with these clinical findings, 12-month old apelin knock-out (Ap

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.

Megakaryocytes (MKs) come from a complex process of hematopoietic progenitor maturation within the bone marrow that gives rise to de novo circulating platelets. Bone marrow microenvironment contains a large number of adipocytes with a still ill-defined role. This study aims to analyze the influence of adipocytes and increased medullar adiposity in megakaryopoiesis. An in vivo increased medullar adiposity in mice caused by high-fat-diet-induced obesity is associated to an enhanced MK maturation and proplatelet formation. In vitro co-culture of adipocytes with bone marrow hematopoietic progenitors shows that delipidation of adipocytes directly supports MK maturation by enhancing polyploidization, amplifying the demarcation membrane system, and accelerating proplatelet formation. This direct crosstalk between adipocytes and MKs occurs through adipocyte fatty acid transfer to MKs involving CD36 to reinforce megakaryocytic maturation. Thus, these findings unveil an influence of adiposity on MK homeostasis based on a dialogue between adipocytes and MKs.

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: Selective dorsal rhizotomy (SDR) used for spasticity treatment could worsen or develop spinal deformities. Our goal is to describe spinal deformities seen in patients with cerebral palsy (CP) after being treated by SDR. Methods: Retrospective study of patients operated on (SDR) between January/1999 and June/2012. Inclusion criteria: spinal Rx before SDR surgery, spinography, and assessment at follow-up. We evaluated several factors emphasizing level and type of SDR approach, spinal deformity and its treatment, final Risser, and follow-up duration. Results: We found 7 patients (6 males): mean age at SDR 7.56 years (4.08-11.16). Mean follow-up: 6.64 years (2.16-13), final age: 14.32 years (7.5-19). No patient had previous deformity. GMFCS: 2 patients level IV, 2 level III, 3 level II. Initial walking status: 2 community walkers, 2 household walkers, 2 functional walkers, 1 not ambulant, at the follow-up, 3 patients improved, and 4 kept their status. We found 4 TL/L laminotomies, 2 L/LS laminectomies, and 1 thoracic laminectomy. Six spinal deformities were observed: 2 sagittal, 3 mixed, and 1 scoliosis. There was no association among the type of deformity, final gait status, topographic type, GMFCS, age, or SDR approach. Three patients had surgery indication for spinal deformity at skeletal maturity, while those patients with smaller deformities were still immature (Risser 0 to 2/3) although with progressive curves. Conclusions: After SDR, patients should be periodically evaluated until they reach Risser 5. The development of a deformity does not compromise functional results but adds morbidity because it may require surgical treatment. RESUMO Objetivo: A rizotomia dorsal seletiva (SDR) para tratamento da espasticidade pode piorar ou desenvolver deformidades da coluna vertebral. Nosso objetivo é descrever as deformidades da coluna observadas em pacientes com paralisia cerebral (PC) depois de serem submetidos à SDR. Métodos: Avaliação retrospectiva de pacientes operados (SDR), entre janeiro/1999 e junho/2012. Critérios de inclusão: Radiografias vertebrais prévias, espinografia e avaliação no acompanhamento. Foram avaliados vários fatores com ênfase no nível e tipo de abordagem da SDR, deformidade da coluna vertebral e seu tratamento, Risser final e tempo de acompanhamento. Resultados: Encontramos 7 pacientes (6 do sexo masculino): média de idade à SDR 7,56 anos (4,08-11,16). Acompanhamento médio: 6,64 anos (2,16-13); idade final: 14,32 anos (7,5-19). Nenhum paciente tinha deformidade anterior. GMFCS: 2 pacientes com nível IV, 2 com nível III, 3 com nível II. Estado deambulatório inicial: 2 deambuladores comunitários, 2 deambuladores domiciliares, 2 deambuladores funcionais, 1 Não deambulador; no acompanhamento, 3 melhoraram e 4 mantiveram seu estado. Foram encontradas 4 laminotomias TL/L, 2 laminectomias L/LS, 1 torácica. Foram detectadas 6 deformidades da coluna: 2 sagitais, 3 mistas e 1 escoliose. Não houve nenhuma associação entre o tipo de deformidade e o estado de deambulação final, tipo topográfico, GMFCS, idade nem abordagem da SDR. Três pacientes tinham indicação de cirurgia à maturidade esquelética, mas as deformidades menores eram ainda imaturas (Risser 0 a 2/3), apesar das curvas evolutivas. Conclusões: A coluna deve-se ser avaliada periodicamente depois da SDR até Risser 5. O desenvolvimento de uma deformidade não afeta o resultado funcional, mas sim acrescenta morbidade, pois pode exigir tratamento cirúrgico. RESUMEN Objetivo: La rizotomía dorsal selectiva (SDR) para el tratamiento de la espasticidad podría empeorar o desarrollar deformidades espinales. Nuestro objetivo es describir deformidades espinales observadas en pacientes con parálisis cerebral (PC) luego de someterse a SDR. Métodos: Evaluación retrospectiva de pacientes operados (SDR) entre enero/1999 y junio/2012. Criterios de inclusión: Rx raquídeas previas, espinograma y evaluación al seguimiento. Se evaluaron diversos factores con énfasis en nivel y tipo de abordaje de SDR, deformidad espinal y su tratamiento, Risser final y tiempo de seguimiento. Resultados: Encontramos 7 pacientes (6 varones): edad promedio a la SDR 7,56 años (4,08 - 11,16). Seguimiento promedio: 6,64 años (2,16 - 13); edad final: 14,32 años (7,5 - 19). Ninguno tenía deformidad previa. GMFCS: 2 pacientes nivel IV, 2 nivel III, 3 nivel II. Estado ambulatorio inicial: 2 Deambuladores Comunitarios, 2 Domiciliarios, 2 Funcionales, 1 No Deambulador; al seguimiento 3 mejoraron y 4 lo mantuvieron. Hubo 4 laminotomías TL/L, 2 laminectomías L/LS y 1 torácica. Se detectaron 6 deformidades espinales: 2 sagitales, 3 mixtas y 1 escoliosis. No hubo asociación entre tipo de deformidad y estado ambulatorio final, tipo topográfico, GMFCS, edad ni abordaje para la SDR. Tres pacientes tuvieron indicación de cirugía; pero estos llegaron a la madurez esquelética, mientras que los de deformidades menores aún son inmaduros (Risser 0 a 2/3) aunque con curvas evolutivas. Conclusiones: Se debe evaluar periódicamente la columna después de SDR hasta Risser 5. La aparición de una deformidad no afecta el resultado funcional pero sí agrega morbilidad pues puede requerir tratamiento quirúrgico.

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.

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.

Cette etude a pour objectif de valider une technique de dosage du glyphosate par polarographie. La premiere partie porte sur l'optimisation de la methode : duree de derivation, concentration et calcul de la detection limite. Les resultats montrent qu'une duree de derivation de deux heures permet d'obtenir un bon compromis entre la rapidite de l'analyse et sa sensibilite. Dans ces conditions, le pourcentage d'erreur est evalue a 3 % et la limite de quantification dans les eaux naturelles est d'environ 40 µg.L-1 et de 0,09 µg.L-1 apres concentration. L'influence de la Matiere Organique Naturelle [Acides Humiques (AH)] a ete etudiee : une legere diminution du coefficient directeur des droites d'etalonnage qui s'attenue avec une augmentation du Carbone Organique Dissout est observee. Enfin le produit commercial est utilise pour determiner si la presence d'adjuvants de formulation entraine des modifications lors du dosage : celle-ci diminue legerement la sensibilite mais aucune variation n'est observee en presence simultanee d'AH.En conclusion, cette methode est relativement rapide et fiable puisque deux heures suffisent pour deriver et doser le glyphosate. De plus cette technique permet de doser le glyphosate en presence d'AH et d'adjuvants de formulation. Une etude similaire pour le dosage du metabolite (AMPA) est actuellement en cours.

In 1934 and 1935 a survey was made of shelterbelts in the Great Plains (Hayes and Stoeckeler, '35) to determine which species had survived the recent drought years, and to study soil adaptability, longevity, and comparative effectiveness of belts of various composition and design. This survey revealed that, on lines of apparently equal effective rainfall, tree plantings in the northern plains had an average life span of about 20 years more than in the central or southern plains. This is explained partly on the basis of a longer growing season in the south and a more rapid exhaustion of the subsoil moisture. Another point of interest was the fact that tree plantings remained thrifty for a much longer time on deep sandy loam soils than on heavy soils such as clays or clay loams. This difference was much more striking in the southern than in the northern plains. Subsequent moisture samplings in the southern plains (Stoeckeler and Bates, '39) revealed a greater supply of available soil moisture in the sandy soils, and this was attributed to higher infiltration rate, relatively deep storage of water, and less evaporation loss. It was also observed that shelterbelts flanked by dense low-growing shrub rows retained their effectiveness longer than open poorly-stocked plantings, because the former more readily attain a dense crown canopy, shade out competing weeds and grass, and retain enough leaves to form a forest floor of litter and humus. It is a matter of common knowledge that dense plantings accumulate a considerable depth of snow in winter, and, since this might be a factor in the growth and longevity of tree belts, a study was made to determine to what extent snow replenished the soil moisture in and near shelterbelts.