Soazig Le Lay

• French Institute of Health and Medical Research

The development of the ovarian follicle requires the presence of several factors that come from the blood and follicular cells. Among these factors, extracellular vesicles (EVs) represent an original communication pathway inside the ovarian follicle. Recently, EVs have been shown to play potential roles in follicular development and reproduction‐re...

Caveolin-1 (CAV1), the main structural component of caveolae, is essential in various biological processes, including mechanotransduction, lipid metabolism, and endocytosis. Deregulation of CAV1 dynamics is linked to various pathologies, including cellular senescence, cancer, insulin resistance, and lipodystrophy. However, mechanisms regulating CAV...

Recent evidence supporting that adipose tissue (AT)-derived extracellular vesicles (EVs) carry an important part of the AT secretome led us to characterize the EV-adipokine profile. In addition to evidencing a high AT-derived EV secretion ability that is further increased by obesity, we identify enrichment of oligomeric forms of adiponectin in smal...

Adipose extracellular vesicles (AdEVs) transport lipids that could participate in the development of obesity-related metabolic dysfunctions. This study aims to define mouse AdEV lipid signature by a targeted LC-MS/MS approach in either healthy or obesity context. Distinct clustering of AdEV and visceral adipose tissue (VAT) lipidomes by principal c...

Lipodystrophies belong to the heterogenous group of syndromes in which the primary defect is a generalized or partial absence of adipose tissue, which may be congenital or acquired in origin. Lipodystrophy should be considered in patients manifesting the combination of insulin resistance (with or without overt diabetes), dyslipidemia and fatty live...

Deficiency of the endoplasmic reticulum (ER) protein seipin results in generalized lipodystrophy by incompletely understood mechanisms. Here, we report mitochondrial abnormalities in seipin-deficient patient cells. A subset of seipin is enriched at ER-mitochondria contact sites (MAMs) in human and mouse cells and localizes in the vicinity of calciu...

Adipose extracellular vesicles (AdEV) transport lipids that could participate to the development of obesity-related metabolic dysfunctions. This study aimed to define mice AdEV lipid signature in either healthy or obesity context by a targeted LC-MS/MS approach. Distinct clustering of AdEV and visceral adipose tissue (VAT) lipidomes by principal co...

Les vésicules extracellulaires (VE) correspondent à un ensemble hétérogène de nanovésicules membranaires sécrétées dans le milieu extracellulaire et circulant dans les différents fluides de l’organisme. Ces VE véhiculent du matériel biologique (protéines, lipides, acides nucléiques) qu’elles peuvent transférer à des cellules/tissus cibles, modulant...

Nutrient excess induces mitochondrial dysfunction, which participates in obesity-related complications. Obesity also associates with high cardiac oxidative stress, which contributes to myocardial dysfunction. Crewe et al. recently evidenced the pivotal role of adipocyte-derived extracellular vesicles (EVs) in cardiac oxidative stress responses and...

Background Metabolic syndrome (MetS) is characterized by a cluster of interconnected risk factors – hyperglycemia, dyslipidemia, hypertension and obesity – leading to an increased risk of cardiovascular events. Small extracellular vesicles (sEVs) can be considered as new biomarkers of different pathologies, and they are involved in intercellular co...

As the largest human energy reservoir, adipocytes drive an intense dialogue with other cells/organs throughout the body to regulate the size of adipose tissue, and to communicate with other metabolic tissues and the brain to regulate energy supply. Adipokines have long been described as mediators of this crosstalk, participating in obesity‐associat...

White adipose tissue (WAT) is involved in long-term energy storage and represents 10–15% of total body weight in healthy humans. WAT secretes many peptides (adipokines), hormones and steroids involved in its homeostatic role, especially in carbohydrate–lipid metabolism regulation. Recently, adipocyte-derived extracellular vesicles (AdEVs) have been...

Background Metabolic syndrome (MetS) is characterized by a cluster of interconnected risk factors -hyperglycemia, dyslipidemia, hypertension and obesity- leading to an increased risk of cardiovascular events. Small extracellular vesicles (sEVs) can be considered as new biomarkers of different pathologies, and they are involved in intercellular comm...

Objective Astrocytes are glial cells proposed as the main Sonic Hedgehog (Shh)-responsive cells in the adult brain. Their roles in mediating Shh functions are still poorly understood. In the hypothalamus, astrocytes support neuronal circuits implicated in the regulation of energy metabolism. Here, we investigated the impact of genetic activation of...

Repetitive complete or incomplete pharyngeal collapses are leading to chronic intermittent hypoxia (CIH), a hallmark feature of obstructive sleep apnea (OSA) syndrome responsible for many metabolic disorders. In humans, an association between OSA and insulin resistance has been found independently of the degree of obesity. Based on our previous wor...

Rationale: Metabolic syndrome (MetS) is a cluster of interrelated risk factors for cardiovascular diseases and atherosclerosis. Circulating levels of large extracellular vesicles (lEVs), submicrometer-sized vesicles released from plasma membrane, from MetS patients were shown to induce endothelial dysfunction but their role in early stage of athero...

Despite long traditional utilization and some reports on the antihyperglycemic and antihyperlipidemic action of Cassia siamea, the mechanisms involved have not been investigated yet. Thus, the objective of the present study was to investigate whether and how oral administration of the ethanolic extract of Cassia siamea Lam leaves (LECS) improves gl...

Despite long traditional utilization and some reports on the antihyperglycemic and antihyperlipidemic action of Cassia siamea, the mechanisms involved have not been investigated yet. Thus, the objective of the present study was to investigate whether and how oral administration of the ethanolic extract of Cassia siamea Lam leaves (LECS) improves gl...

Introduction The metabolic syndrome (MetS) is characterized by the association of several disorders that increase the risk of developing cardiovascular diseases and insulin resistance. In addition to the development of type II diabetes, insulin resistance can also lead to many complications such as atherosclerosis, dyslipidemia and high blood press...

Extracellular vesicles (EVs) are emerging as a novel way of cell-to-cell communication and represent an attractive way to convey fundamental information between cells. EVs, released in the extracellular space, circulate via the various body fluids and modulate locally or remotely the cellular responses following their interaction with the target ce...

Objective Obesity-associated metabolic dysfunctions are linked to dysregulated production of adipokines. Accumulating evidence suggests a role for fat-derived extracellular vesicles (EVs) in obesity-metabolic disturbances. Since EVs convey numerous proteins we aimed to evaluate their contribution in adipokine secretion. Methods Plasma collected fr...

Cardiovascular disease (CVD) constitutes one of the leading causes of mortality worldwide, therefore representing a major public health concern. Despite recent advances in the treatment of patients with acute myocardial infarction (AMI), such as bypass surgery or percutaneous coronary intervention, pathological cardiac remodeling often predisposes...

Delphinidin, an anthocyanin present in red wine, has been reported to preserve the integrity of endothelium via an estrogen receptor alpha (ERα)-dependent mechanism. However, the effect of delphinidin on the immune response in obesity-related inflammation remains unknown. Given the important role of T lymphocytes in obesity-related inflammation, we...

Lipin-1 is a Mg2+-dependent phosphatidic acid phosphatase (PAP) that in mice is necessary for normal glycerolipid biosynthesis, controlling adipocytes metabolism and adipogenic differentiation. Mice carrying inactivating mutations in the Lpin1 gene display the characteristic features of human familial lipodystrophy. Very little is known on the role...

Extracellular vesicles (EVs) are biological vectors that can modulate the metabolism of target cells by conveying signalling proteins and genomic material. The level of EVs in plasma is significantly increased in cardiometabolic diseases associated with obesity, suggesting their possible participation in the development of metabolic dysfunction. Wi...

Extracellular vesicles (EVs) are biological vectors that can modulate the metabolism of target cells by conveying signalling proteins and genomic material. The level of EVs in plasma is significantly increased in cardiometabolic diseases associated with obesity, suggesting their possible partici- pation in the development of metabolic dysfunction....

Proteomic profiling of extracellular vesicles derived from adipocytes reveals the presence of key metabolic proteins involved in the development of cardiovascular diseases associated with obesity

Fibroblast growth factor 21 (FGF21) was shown to improve metabolic homeostasis, at least partly by controlling white adipocyte profile and adiponectin secretion. Here, we studied its effect on adipocyte dysfunction in the context of Berardinelli-Seip Congenital Lipodystrophy (BSCL) linked to seipin-deficiency. Bscl2(-/-) mice displayed a progressiv...

Hedgehog (Hh) is a critical regulator of adipogenesis. Extracellular vesicles are natural Hh carriers, as illustrated by activated/apoptotic lymphocytes specifically shedding microparticles (MP) bearing the morphogen (MP(Hh+)). We show that MP(Hh+) inhibit adipocyte differentiation and orientate mesenchymal stem cells towards a pro-osteogenic progr...

Introduction Les vésicules extracellulaires (VE) constituent des vecteurs biologiques capables de moduler le métabolisme de cellules cibles de par leur capacité à véhiculer des protéines de signalisation. Le taux de VE plasmatiques est significativement augmenté dans les pathologies cardiométaboliques associées à l'obésité suggérant leur éventuelle...

Objectif Le morphogène Sonic Hedgehog (Shh) diffuse dans l’organisme sous forme libre ou associée à des vésicules extracellulaires. Nos travaux montrent que certains types de MVs véhiculant spécifiquement Shh peuvent corriger la dysfonction endothéliale souvent associée aux pathologies cardiovasculaires. Shh a aussi été identifié comme un facteur a...

During obesity, an hypoxic state develops within the adipose tissue resulting in insulin resistance. In order to understand the underlying mechanism, we analyzed the involvement of caveolae, since they play crucial role in the activation of insulin receptors. In the present study, we demonstrate that in 3T3-L1 adipocytes, hypoxia induces the disapp...

The role of ATP-binding Cassette G1 (ABCG1) transporter in human pathophysiology is still largely unknown. Indeed, beyond its role in mediating free cholesterol efflux to HDL, ABCG1 transporter equally promotes lipid accumulation in a triglyceride (TG)-rich environment through regulation of the bioavailability of Lipoprotein Lipase (LPL).As both AB...

Extracellular vesicles (EVs), including microvesicles (MVs) and exosomes, are small vesicles secreted from a wide variety of cells. Whereas MVs are particles released by the outward budding of the plasma membrane, exosomes are derived from endocytic compartments. Secretion of EVs can be enhanced by specific stimuli, and increased plasma circulating...

Oxidative stress plays a pathological role in the development of various diseases including diabetes, atherosclerosis, or cancer. Systemic oxidative stress results from an imbalance between oxidants derivatives production and antioxidants defenses. Reactive oxygen species (ROS) are generally considered to be detrimental for health. However, evidenc...

Adipocytes specialized in the storage of energy as fat are among the most caveolae-enriched cell-types. Loss of caveolae produces lipodystrophic diabetes in humans, which cannot be reversed by endothelial rescue of caveolin expression in mice, indicating major importance of adipocyte caveolae. However, how caveolae participate in fat cell functions...

Introduction Lors de l’obésité le développement de zones d’hypoxie dans le tissu adipeux est impliqué dans le développement de la résistance à l’insuline en inhibant la voie de signalisation de l’insuline dans les adipocytes. L’activation du récepteur de l’insuline dépend de sa localisation dans les cavéoles, dont la formation et la fonction sont c...

Recent data indicate that cell size fluctuation, a key property in adipocyte pathophysiology primarily dependent on lipid storage, is linked to a novel function of lipid droplet organelles acting as mechano-active organelles to regulate cell membrane remodeling and caveolae dynamics.

Cytoplasmic lipid droplets are now recognized as dynamic and regulated intracellular organelles that play active role in fatty acid storage and mobilization. This chapter briefly summarizes present knowledge on lipid droplet lifetime, and gives a special emphasis on adipocyte lipid droplets. Their uniqueness and specific properties are discussed as...

La gestion de l’énergie est une question cruciale pour les cellules et un stockage transitoire apparaît comme une stratégie adaptée pour pallier les périodes de privation nutritionnelle. à cet égard, toutes les cellules eucaryotes, de la levure aux cellules de mammifères, ont développé la capacité potentielle d’accumuler des lipides et de former de...

Lipophilic pollutants such as polychlorinated biphenyls (PCBs) accumulate in high amounts in the adipose tissue. Recent epidemiological studies correlate their presence in fat cells to possible alterations in the regulation of lipid metabolism. The factors governing their accumulation dynamics, storage and release in/from fat cells remain however u...

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that preferentially accumulate in lipid-rich tissues of contaminated organisms. Although the adipose tissue constitutes a major intern reservoir of PCBs and recent epidemiological studies associate PCBs to the development of obesity and its related disorders, little is known a...

Caveolin-1 (Cav1), a structural protein required for the formation of invaginated membrane domains known as caveolae, has been implicated in cholesterol trafficking and homeostasis. Here we investigated the contribution of Cav1 to apolipoprotein A-I (apoA-I) cell surface binding and intracellular processing using mouse embryonic fibroblasts (MEFs)...

Objectif Il est maintenant établi qu’une déficience en cavéoline (par mutation primaire du gène CAV-1 ou due à un défaut secondaire du gène PTRF/Cavin cause un diabète lipoatrophique chez les patients. Étant donné la très forte expression des cavéolines dans les cellules de l’endothélium vasculaire et dans les adipocytes, nous avons voulu évaluer l...

Caveolae are flask-shaped invaginations in the plasma membrane that serve to compartmentalize and organize signal transduction processes, including signals mediated by G protein-coupled receptors and heterotrimeric G proteins. Herein we report evidence for a close association of the nucleoside diphosphate kinase B (NDPK B) and caveolin proteins whi...

Defective caveolin-1 expression is now recognized as a cause of lipoatrophic diabetes in patients, due to primary caveolin gene mutations or secondary caveolin deficiency caused by PTRF/cavin gene defects. The goal of this study was to establish the relative contribution of endothelial cells and adipocytes, both highly expressing caveolin-1 to the...

Adipose tissue lipoatrophy caused by caveolin gene deletion in mice is not linked to defective adipocyte differentiation. We show that adipose tissue development cannot be rescued by endothelial specific caveolin-1 re-expression, indicating primordial role of caveolin in mature adipocytes. Partial or total caveolin deficiency in adipocytes induced...

Caveolae are specialized lipid microdomains, forming small invaginations in the plasma membrane, known to be implicated in multiple functions including lipid storage, cell signaling and endocytosis. Formation of these wide flask-shaped invaginations is dependent on the expression of a caveolar coat protein, namely caveolin. Until now, the accepted...

Caveolins form plasmalemnal invaginated caveolae. They also locate around intracellular lipid droplets but their role in this location remains unclear. By studying primary adipocytes that highly express caveolin-1, we characterized the impact of caveolin-1 deficiency on lipid droplet proteome and lipidome. We identified several missing proteins on...

Lipid rafts defined as cholesterol- and sphingomyelin-rich domains have been isolated from different cell types that vary greatly in their lipid profiles. Here, we investigated the contribution of the structural protein caveolin-1 (Cav1) to the overall lipid composition and domain abundance in mouse embryonic fibroblasts (MEFs) from wild-type (WT)...

In the recent years, new advances in the biology of lipid droplets led these structures specialized for lipid storage to be considered as new universal intracellular organelles playing active roles in cell physiology. Concomitantly, studies on the pathogenesis of metabolic diseases such as type 2 diabetes or atherosclerosis, associated with ongoing...

Caveolins are primarily known as the main constituents of the protein coat of caveolae invaginations at the plasma membrane. They have also been found at the surface of intracellular lipid droplets but their function in this lipid storage organelle remains poorly understood. This paper reviews recent studies in adipocytes, the specialized cell type...

Caveolins, structural protein coats of caveolae primarily involved in membrane-related functions, have also been found associated to lipid droplets (LD), specialized organelles for fat storage. In the present study, we wanted to delineate the main features that govern the presence of caveolin-1 on adipocyte lipid droplets. Using either morphologica...

Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare recessive disease characterized by near absence of adipose tissue, resulting in severe dyslipidemia and insulin resistance. In most reported cases, BSCL is due to alterations in either seipin, of unknown function, or 1-acylglycerol-3-phosphate acyltransferase-beta (AGPAT2), which catalyzes...

Caveolae are specialized membrane microdomains formed as the result of local accumulation of cholesterol, glycosphingolipids, and the structural protein caveolin-1 (Cav-1). To further elucidate the role of Cav-1 in lipid homeostasis in-vivo, we analyzed fasting and post-prandial plasma from Cav-1 deficient mice on low or on high fat diet. In total...

Elevated ceramide concentrations in adipocytes and skeletal muscle impair PKB (protein kinase B; also known as Akt)-directed insulin signalling to key hormonal end points. An important feature of this inhibition involves the ceramide-induced activation of atypical PKCzeta (protein kinase C-zeta), which associates with and negatively regulates PKB....

Introduction La lipodystrophie congénitale de Berardinelli-Seip (BSCL) est une maladie rare caractérisée par une quasi-absence de tissu adipeux et une insulino-résistance sévère. Elle est transmise de façon récessive et résulte, dans environ 95 % des cas, de mutations de BSCL2, le gène codant la seipine ou de AGPAT2, codant la 1-acylglycérol-3-P ac...

Lipid rafts are liquid ordered platforms that dynamically compartmentalize membranes. Caveolins and flotillins constitute a group of proteins that are enriched in these domains. Caveolin-1 has been shown to be an essential component of caveolae. Flotillins were also discovered as an integral component of caveolae and have since been suggested to in...

The properties of cholesterol-dependent domains (lipid rafts) in cell membranes have been controversial. Because integrin-mediated cell adhesion and caveolin both regulate trafficking of raft components, we investigated the effects of adhesion and caveolin on membrane order. The fluorescent probe Laurdan and two-photon microscopy revealed that foca...

We have investigated the targeting of caveolin to lipid bodies in adipocytes that express high levels of caveolins and contain well-developed lipid droplets. We observed that the lipid droplets isolated from adipocytes of caveolin-1 knock out mice contained dramatically reduced levels of cholesterol, indicating that caveolin is required for maintai...

Several lines of evidence suggest that lipid rafts are involved in cellular fatty acid uptake and influence fatty acid translocase (FAT/CD36) function. However, it remains unknown whether caveolae, a specialized raft type, are required for this mechanism. Here, we show that wild-type (WT) mouse embryonic fibroblasts (MEFs) and caveolin-1 knockout (...

The elucidation of the role of caveolae has been the topic of many investigations which were greatly enhanced after the discovery of caveolin, the protein marker of these flask-shaped plasma membrane invaginations. The generation of mice deficient in the various caveolin genes (cav-1, cav-2 and cav-3) has provided physiological models to unravel th...

Caveolin-1 has been implicated in apical transport of glycosylphosphatidylinositol (GPI)-anchored proteins and influenza virus hemagglutinin (HA). Here we have studied the role of caveolin-1 in apical membrane transport by generating caveolin-1-deficient Madin-Darby canine kidney (MDCK) cells using retrovirus-mediated RNA interference. The caveolin...

Adipose tissue is specialized in the storage of energy in the form of triacylglycerol. Within the fat cell, triacylglycerols are found in a well-defined structural compartment called the lipid droplet, which occupies the vast majority of the fat cell volume. However, many other lipids are present in the lipid droplet. These include sterols, caroten...

Adipose cells specialized in energy storage, contain large intracellular triglyceride-rich lipid droplets, are enriched with free cholesterol, and express sterol-regulated transcription factors such as liver X receptor (LXR). The recent identification of the LXR-dependent ATP binding cassette transporter A1 (ABCA1) pathway for cholesterol release f...

In recent years, our view of adipose tissue has evolved from a passive sink for energy storage to an active tissue producing multiple molecules acting on various tissues in different aspects of energy homeostasis. The production of adipose-derived secretory products is tightly regulated as a function of adipocyte lipid accumulation, but the mechani...

Catecholamines regulate white adipose tissue function and development by acting through beta- and alpha2-adrenergic receptors (ARs). Human adipocytes express mainly alpha 2A- but few or no beta 3-ARs while the reverse is true for rodent adipocytes. Our aim was to generate a mouse model with a human-like alpha2/beta-adrenergic balance in adipose tis...

The presence of a neuropeptide AF and FF receptor (NPFF-R2) mRNA in human adipose tissue (Elshourbagy, N. A., Ames, R. S., Fitzgerald, L. R., Foley, J. J., Chambers, J. K., Szekeres, P. G., Evans, N. A., Schmidt, D. B., Buckley, P. T., Dytko, G. M., Murdock, P. R., Tan, K. B., Shabon, U., Nuthulaganti, P., Wang, D. Y., Wilson, S., Bergsma, D. J., a...

We evaluated the hypothesis of sterol-regulatory element-binding protein (SREBP)-1c being a general mediator of the transcriptional effects of insulin, with a focus on adipocytes, in which insulin profoundly influences specific gene expression. Using real time quantitative reverse transcriptase-PCR to monitor changes in the expression of about 50 g...

Sterol regulatory element binding protein-1c (SREBP-1c) is a transcription factor that mediates insulin effects on hepatic gene expression. It is itself transcriptionally stimulated by insulin in hepatocytes. Here we show that SREBP-1c mRNA is expressed in adult rat skeletal muscles and that this expression is decreased by diabetes. The regulation...

The regulation of resistin, a new adipose-derived circulating factor, is the subject of controversy. In particular, the question of its modulation in obesity led to opposite results reported by two different groups. In the current study, we assayed adipocyte resistin mRNA using fluorescent real-time RT-PCR. We studied the expression of resistin in...