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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-related disorders, including the polycystic ovary syndrome (PCOS). The proteomic analysis of sEVs isolated from FF in comparison to sEVs purified from plasma has shown a specific pattern of proteins secreted by ovarian steroidogenic cells such as granulosa cells. Thus, a human granulosa cell line exposed to sEVs from FF of normal patients increased their progesterone, estradiol, and testosterone secretion. However, if the sEVs were derived from FF of PCOS patients, the activity of stimulating progesterone production was lost. Stimulation of steroidogenesis by sEVs was associated with an increase in the expression of the StAR gene. In addition, sEVs from FF increased cell proliferation and migration of granulosa cells, and this phenomenon was amplified if sEVs were derived from PCOS patients. Interestingly, STAT3 is a protein overexpressed in sEVs from PCOS patients interacting with most of the cluster of proteins involved in the phenotype observed (cell proliferation, migration, and steroid production) in granulosa cells. In conclusion, this study has demonstrated that sEVs derived from FF could regulate directly the granulosa cell activity. The protein content in sEVs from FF is different in the case of PCOS syndrome and could perturb the granulosa cell functions, including inflammation, steroidogenesis, and cytoskeleton architecture., (© 2024 Federation of American Societies for Experimental Biology.)

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 small EVs (sEVs). This adipokine is mainly distributed at the EV external surface as a result of nonspecific adsorption of soluble adiponectin. EVs also constitute stable conveyors of adiponectin in the blood circulation. Adiponectin-enriched sEVs display in vitro insulin-sensitizing effects by binding to regular adiponectin receptors. Adoptive transfer of adiponectin-enriched sEVs in high-fat-diet-fed mice prevents animals from gaining weight and ameliorated insulin resistance and tissue inflammation, with major effects observed in the AT and liver. Our results therefore provide information regarding adiponectin-related metabolic responses by highlighting EVs as delivery platforms of metabolically active forms of adiponectin molecules., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

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 component analysis reveals specific AdEV lipid sorting when compared with secreting VAT. Comprehensive analysis identifies enrichment of ceramides, sphingomyelins, and phosphatidylglycerols species in AdEVs compared with source VAT whose lipid content closely relates to the obesity status and is influenced by the diet. Obesity moreover impacts AdEV lipidome, mirroring lipid alterations retrieved in plasma and VAT. Overall, our study identifies specific lipid fingerprints for plasma, VAT, and AdEVs that are informative of the metabolic status. Lipid species enriched in AdEVs in the obesity context may constitute biomarker candidates or mediators of the obesity-associated metabolic dysfunctions., Competing Interests: Declaration of interests There are no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Intervertebral disc degeneration (IDD) involves cellular changes in the nucleus pulposus (NP) characterised by a decline of the large vacuolated notochordal cells (vNCs) and a rise of smaller vacuole-free mature chondrocyte-like NP cells. An increasing number of studies demonstrate that notochordal cells (NCs) exert disease-modifying effects, establishing that NC-secreted factors are essential for the maintenance of a healthy intervertebral disc (IVD). However, understanding the role of the NCs is hampered by a restricted reserve of native cells and the lack of robust ex vivo cell model. A precise dissection enabled the isolation of NP cells from 4 d post-natal stage mouse spines and their culture into self-organised micromasses. The maintenance of cells' phenotypic characteristics was demonstrated by the presence of intracytoplasmic vacuoles and the immuno-colocalisation of the NC-markers (brachyury; SOX9) after 9 d of culture both in hypoxic and normoxic conditions. A significant increase of the size of the micromass was observed under hypoxia, consistent with a higher level of Ki-67+ immunostained proliferative cells. Furthermore, several proteins of interest for the study of vNCs phenotype (CD44; caveolin-1; aquaporin 2; patched-1) were successfully detected at the plasma membrane of NP-cells cultured in micromasses under hypoxic condition. IHC was performed on mouse IVD sections as control staining. An innovative 3D culture model of vNCs derived from mouse postnatal NP is proposed, allowing future ex vivo exploration of their basic biology and of the signalling pathways involved in IVD homeostasis that may be relevant for disc repair.

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 liver. Lipodystrophies are classified according to the etiology of the disease (genetic or acquired) and to the anatomical distribution of adipose tissue (generalized or partial). The mechanism of adipose tissue loss is specific to each syndrome, depending on the biological function of the mutated gene. Mice models, together with cellular studies have permitted clarification of the mechanisms by which human mutations deeply compromise adipocyte homeostasis. In addition, rodent models have proven to be crucial in deciphering the cardiometabolic consequences of the lack of adipose tissue such as NAFLD, muscle insulin resistance and cardiomyopathy. More precisely, tissue-specific transgenic and knockout mice have brought new tools to distinguish phenotypic traits that are the consequences of lipodystrophy from those that are cell-autonomous. In this review, we discuss the mice models of lipodystrophy including those of inherited human syndromes of generalized and partial lipodystrophy. We present how these models have demonstrated the central role of white adipose tissue in energetic homeostasis in general, including insulin sensitivity and lipid handling in particular. We underscore the differences reported with the human phenotype and discuss the limit of rodent models in recapitulating adipose tissue primary default. Finally, we present how these mice models have highlighted the function of the causative-genes and brought new insights into the pathophysiology of the cardiometabolic complications associated with lipodystrophy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Le Lay, Magré and Prieur.)

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 calcium regulators SERCA2, IP3R, and VDAC. Seipin association with MAM calcium regulators is stimulated by fasting-like stimuli, while seipin association with lipid droplets is promoted by lipid loading. Acute seipin removal does not alter ER calcium stores but leads to defective mitochondrial calcium import accompanied by a widespread reduction in Krebs cycle metabolites and ATP levels. In mice, inducible seipin deletion leads to mitochondrial dysfunctions preceding the development of metabolic complications. Together, these data suggest that seipin controls mitochondrial energy metabolism by regulating mitochondrial calcium influx at MAMs. In seipin-deficient adipose tissue, reduced ATP production compromises adipocyte properties, contributing to lipodystrophy pathogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

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 revealed their unexpected protective effect against ischemia/reperfusion injury., Competing Interests: Declaration of interests None declared by authors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Extracellular vesicles (EVs) correspond to a heterogeneous set of membrane nanovesicles secreted in the extracellular medium and circulating in the various fluids of the body. These EVs convey biological material (proteins, lipids, nucleic acids) that they can transfer to target cells/tissues thus modulating their response and/or phenotype. The metabolic dysfunctions characterizing metabolic diseases associated with obesity are associated with changes in circulating EV concentrations as well as alterations in their content. The growing interest in EVs as new vectors of intercellular communication has led to question about their role in the development of metabolic complications. In this review, we will discuss the literature on circulating EVs as potential markers of metabolic diseases and then detail inter-organ dialogue based on this EV trafficking underlying the development of related obesity. Finally, we will discuss future avenues of research that will help to better understand the link between EVs and metabolic diseases., (© 2021 médecine/sciences – Inserm.)

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. In this study, we investigated the impact of genetic activation of Shh signaling on hypothalamic astrocytes and characterized its effects on energy metabolism., Methods: We analyzed the distribution of gene transcripts of the Shh pathway (Ptc, Gli1, Gli2, and Gli3) in astrocytes using single molecule fluorescence in situ hybridization combined with immunohistofluorescence of Shh peptides by Western blotting in the adult mouse hypothalamus. Based on the metabolic phenotype, we characterized Glast-Cre ERT2 -YFP-Ptc -/- (YFP-Ptc -/- ) mice and their controls over time and under a high-fat diet (HFD) to investigate the potential effects of conditional astrocytic deletion of the Shh receptor Patched (Ptc) on metabolic efficiency, insulin sensitivity, and systemic glucose metabolism. Molecular and biochemical assays were used to analyze the alteration of key pathways modulating energy metabolism, insulin sensitivity, glucose uptake, and inflammation. Primary astrocyte cultures were used to evaluate a potential role of Shh signaling in astrocytic glucose uptake., Results: Shh peptides were the highest in the hypothalamic extracts of adult mice and a large population of hypothalamic astrocytes expressed Ptc and Gli1-3 mRNAs. Characterization of Shh signaling after conditional Ptc deletion in the YFP-Ptc -/- mice revealed heterogeneity in hypothalamic astrocyte populations. Interestingly, activation of Shh signaling in Glast + astrocytes enhanced insulin responsiveness as evidenced by glucose and insulin tolerance tests. This effect was maintained over time and associated with lower blood insulin levels and also observed under a HFD. The YFP-Ptc -/- mice exhibited a lean phenotype with the absence of body weight gain and a marked reduction of white and brown adipose tissues accompanied by increased whole-body fatty acid oxidation. In contrast, food intake, locomotor activity, and body temperature were not altered. At the cellular level, Ptc deletion did not affect glucose uptake in primary astrocyte cultures. In the hypothalamus, activation of the astrocytic Shh pathway was associated with the upregulation of transcripts coding for the insulin receptor and liver kinase B1 (LKB1) after 4 weeks and the glucose transporter GLUT-4 after 32 weeks., Conclusions: Here, we define hypothalamic Shh action on astrocytes as a novel master regulator of energy metabolism. In the hypothalamus, astrocytic Shh signaling could be critically involved in preventing both aging- and obesity-related metabolic disorders., Competing Interests: Conflicts of interest The authors have no competing interests to declare., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

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 communication. Here, we hypothesize that sEVs are implicated in MetS-associated endothelial dysfunction., Methods: Circulating sEVs of non-MetS (nMetS) subjects and MetS patients were isolated from plasma and characterized. Thereafter, sEV effects on endothelial function were analyzed by measuring nitric oxide (NO) and reactive oxygen species (ROS) production, and mitochondrial dynamic proteins on human endothelial aortic cells (HAoECs)., Results: Circulating levels of sEVs positively correlated with anthropometric and biochemical parameters including visceral obesity, glycaemia, insulinemia, and dyslipidemia. Treatment of HAoECs with sEVs from MetS patients decreased NO production through the inhibition of the endothelial NO-synthase activity. Injection of MetS-sEVs into mice impaired endothelium-dependent relaxation induced by acetylcholine. Furthermore, MetS-sEVs increased DHE and MitoSox-associated fluorescence in HAoECs, reflecting enhanced cytosolic and mitochondrial ROS production which was not associated with mitochondrial biogenesis or dynamic changes. MetS patients displayed elevated circulating levels of LPS in plasma, and, at least in part, it was associated to circulating sEVs. Pharmacological inhibition and down-regulation of TLR4, as well as sEV-carried LPS neutralization, results in a substantial decrease of ROS production induced by MetS-sEVs., Conclusion: These results evidence sEVs from MetS patients as potential new biomarkers for this syndrome, and TLR4 pathway activation by sEVs provides a link between the endothelial dysfunction and metabolic disturbances described in MetS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

As the largest human energy reservoir, adipocytes drive an intense dialog 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-associated complications. Recently, adipocyte-derived extracellular vesicles (Ad-EVs) have emerged as new key actors in this communication due to their powerful capacity to convey complex messages between cells. Ad-EVs convey specific subpopulations of RNA, proteins, and lipids from their parental cells, and can transfer these cargoes into various recipient cells, modulating their metabolism and cell cycle. In healthy individuals, Ad-EVs actively participate in adipose tissue remodeling to compensate energy supply variations by exchanging information between adipocytes or stroma-vascular cells, including immune cells. Besides this, recent evidence points out that Ad-EV secretion and composition from dysfunctional adipocytes are strongly impacted within adipose tissue where they modulate local intercellular communication, contributing to inflammation, fibrosis, abnormal angiogenesis, and at distance with other cells/tissues intrinsically linked to fat (muscle, hepatocytes and even cancer cells). Additionally, some data even suggests that Ad-EVs might have a systemic action. In this review, we will describe the particular properties of Ad-EVs and their involvement in health and diseases, with a particular focus on metabolic and cardiovascular diseases as well as cancer., Competing Interests: There are no conflicts of interest to declare., (© 2021 The Authors. FASEB BioAdvances published by the Federation of American Societies for Experimental Biology.)

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 highlighted as important actors of intercellular communication that participate in metabolic responses to control energy flux and immune response. In this review, we focus on the role of AdEVs in the cross-talks between the different cellular types composing WAT with regard to their contribution to WAT homeostasis and metabolic complications development. We also discuss the AdEV cargoes (proteins, lipids, RNAs) which may explain AdEV's biological effects and demonstrate that, in terms of proteins, AdEV has a very specific signature. Finally, we list and suggest potential therapeutic strategies to modulate AdEV release and composition in order to reduce their deleterious effects during the development of metabolic complications associated with obesity.

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 work showing that hypoxia applied to adipocytes led to cellular insulin resistance associated with caveolae flattening, we have investigated the effects of CIH on caveolae structuration in adipose tissue. Original exploratory experiences demonstrate that 6 weeks-exposure of lean mice to CIH is characterized by systemic insulin resistance and translates into adipocyte insulin signaling alterations. Chronic intermittent hypoxia also induces caveolae disassembly in white adipose tissue (WAT) illustrated by reduced plasma membrane caveolae density and enlarged caveolae width, concomitantly to WAT insulin resistance state. We show that CIH downregulates caveolar gene and protein expressions, including cavin-1, cavin-2, and EHD2, underlying molecular mechanisms responsible for such caveolae flattening. Altogether, we provide evidences for adipose tissue caveolae disassembly following CIH exposure, likely linked to cavin protein downregulation. This event may constitute the molecular basis of insulin resistance development in OSA patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Varela-Guruceaga, Belaidi, Lebeau, Aka, Andriantsitohaina, Giorgetti-Peraldi, Arnaud and Le Lay.)

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 atherosclerosis and on vascular smooth muscle cells (SMC) remain to be fully elucidated., Objective: To determine the mechanisms by which lEVs lead to the progression of atherosclerosis in the setting of MetS., Methods and Results: Proteomic analysis revealed that the small GTPase, Rap1 was overexpressed in lEVs from MetS patients compared with those from non-MetS subjects. Rap1 was in GTP-associated active state in both types of lEVs, and Rap1-lEVs levels correlated with increased cardiovascular risks, including stenosis. MetS-lEVs, but not non-MetS-lEVs, increased Rap1-dependent endothelial cell permeability. MetS-lEVs significantly promoted migration and proliferation of human aortic SMC and increased expression of proinflammatory molecules and activation of ERK (extracellular signal-regulated kinase) 5/p38 pathways. Neutralization of Rap1 by specific antibody or pharmacological inhibition of Rap1 completely prevented the effects of lEVs from MetS patients. High-fat diet-fed ApoE -/- mice displayed an increased expression of Rap1 both in aortas and circulating lEVs. lEVs accumulated in plaque atherosclerotic lesions depending on the progression of atherosclerosis. lEVs from high-fat diet-fed ApoE -/- mice, but not those from mice fed with a standard diet, enhanced SMC proliferation. Human atherosclerotic lesions were enriched in lEVs expressing Rap1., Conclusions: These data demonstrate that Rap1 carried by MetS-lEVs participates in the enhanced SMC proliferation, migration, proinflammatory profile, and activation of ERK5/p38 pathways leading to vascular inflammation and remodeling, and atherosclerosis. These results highlight that Rap1 carried by MetS-lEVs may be a novel determinant of diagnostic value for cardiometabolic risk factors and suggest Rap1 as a promising therapeutic target against the development of atherosclerosis. Graphical Abstract: A graphical abstract is available for this article.

Caveolae are an abundant, but enigmatic, plasma membrane feature of vertebrate cells. In this brief commentary, the authors attempt to answer some key questions related to the formation and function of caveolae based on round-table discussions at the first EMBO Workshop on Caveolae held in France in May 2019., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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 glucose and insulin homoeostasis, liver damage, and endothelial dysfunction in an experimental model of type 2 diabetes, the leptin-deficient ob/ob mice. Oxidative stress and protein expression of insulin-dependent and insulin -independent signaling pathways were studied. Obese ( ob/ob ) vs. control ( ob/+ ) mice were treated daily with intragastric administration of either vehicle or LECS (200 mg/kg, per day) for 4 weeks. Fasting blood glucose, body weight, food intake, glucose and insulin tolerance, oxidative stress, and liver damage as well as vascular complications with respect to endothelial dysfunction were examined. Administration of LECS in obese mice significantly reduced blood glucose and insulin levels, improved glucose tolerance and insulin sensitivity, and restored the increase of circulating AST and ALT without modification of body weight and food intake. These effects were associated with increased activity of both insulin and AMPK pathways in the liver and skeletal muscles. Of particular interest, administration of LECS in obese mice completely prevented the endothelial dysfunction resulting from an increased NO · and decreased reactive oxygen species (ROS) production in the aorta. Altogether, oral administration of LECS remarkably attenuates features of type 2 diabetes on glucose, hepatic inflammation, insulin resistance, endothelial function, and vascular oxidative stress, being as most of these effects are related to insulin-dependent and insulin-independent mechanisms. Therefore, this study points for the therapeutic potential of Cassia siamea in correcting both metabolic and vascular alterations linked to type 2 diabetes., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2019 Camille Koffi et al.)

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 from metabolic syndrome patients were used to isolate EV subtypes, namely microvesicles (MVs) and exosomes (EXOs). Numerous soluble factor concentrations were measured successively on total, MV- and EXO-depleted plasma by multiplexed immunoassays., Results: Circulating MVs and EXOs were significantly increased with BMI, supporting a role of EVs as metabolic relays in obesity. Obesity was associated with dysregulated soluble factor production. Sequential depletion of plasma MVs and EXOs did not modify plasma levels of these molecules, with the exception of Macrophage Migration Inhibitory Factor (MIF). Half of plasma MIF circulated within MVs, and this MV secretory pathway was conserved over different MIF-producing cells. Although MV-associated MIF triggered rapid ERK1/2 activation in macrophages, these functional MV-MIF effects specifically relied on MIF tautomerase activity., Conclusion: Our results emphasize the importance of reconsidering MIF-metabolic actions with regard to its MV-associated form and opening new EV-based strategies for therapeutic MIF approaches., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)

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 cells. Clinical and experimental data support their role as biomarkers and bioeffectors in diseases related to the metabolic syndrome. EVs thus hustle the traditional vision of intercellular communication, via an alternative and versatile mode of communication, and open the door to new concepts and opportunities from a therapeutic and biological point of view., (© 2018 médecine/sciences – Inserm.)

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 survivors to fatal heart failure. In this context, the proven efficacy of stem cell-regenerative therapies constitutes a promising therapeutic perspective with is nevertheless slow down by safety and ethical concerns. Recent studies have underscored the capacity of stem cell-derived extracellular vesicles (EV) to recapitulate the regenerative properties of their parental cells therefore offering a therapeutic alternative to cell therapy in cardiovascular regenerative medicine. In this article, we review the functional relevance of using stem cell-derived EV as therapeutically agents and detail the identified molecular pathways that they used to exert their effects. We also discuss the advantages of using such an acellular regenerative therapy, in regard with parental stem cells, and address the limitations, which would need to be resolved, before their clinical translation., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Lipin-1 is a Mg 2+ -dependent phosphatidic acid phosphatase (PAP) that in mice is necessary for normal glycerolipid biosynthesis, controlling adipocyte metabolism, and adipogenic differentiation. Mice carrying inactivating mutations in the Lpin1 gene display the characteristic features of human familial lipodystrophy. Very little is known about the roles of lipin-1 in human adipocyte physiology. Apparently, fat distribution and weight is normal in humans carrying LPIN1 inactivating mutations, but a detailed analysis of adipose tissue appearance and functions in these patients has not been available so far. In this study, we performed a systematic histopathological, biochemical, and gene expression analysis of adipose tissue biopsies from human patients harboring LPIN1 biallelic inactivating mutations and affected by recurrent episodes of severe rhabdomyolysis. We also explored the adipogenic differentiation potential of human mesenchymal cell populations derived from lipin-1 defective patients. White adipose tissue from human LPIN1 mutant patients displayed a dramatic decrease in lipin-1 protein levels and PAP activity, with a concomitant moderate reduction of adipocyte size. Nevertheless, the adipose tissue develops without obvious histological signs of lipodystrophy and with normal qualitative composition of storage lipids. The increased expression of key adipogenic determinants such as SREBP1 , PPARG , and PGC1A shows that specific compensatory phenomena can be activated in vivo in human adipocytes with deficiency of functional lipin-1., (Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.)

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 investigated the effect of delphinidin on proliferation and differentiation of T lymphocytes from healthy subjects and metabolic syndrome patients. Delphinidin decreased the proliferation stimulated by different agents acting through different mechanisms. This effect of delphinidin was associated with its ability to inhibit Ca 2+ signaling via reduced store-operated Ca 2+ entry and release, and subsequent decrease of HDAC and NFAT activations. Delphinidin also inhibited ERK1/2 activation. Pharmacological inhibition of ER with fulvestrant, or deletion of ERα, prevented the effect of delphinidin. Further, delphinidin suppressed the differentiation of T cells toward Th1, Th17 and Treg without affecting Th2 subsets. Interestingly, delphinidin inhibited both proliferation and differentiation of T cells taken from patients with cardiovascular risks associated with metabolic syndrome. Together, we propose that delphinidin, by acting on ERα via multiple cellular targets, may represent a new approach against chronic inflammation associated with T lymphocyte activation, proliferation and differentiation, in patients with cardiovascular risk factors.