Publications by authors named "Philippe Valet"

135 Publications

The Chemokine Receptor CCR3 Is Potentially Involved in the Homing of Prostate Cancer Cells to Bone: Implication of Bone-Marrow Adipocytes.

Int J Mol Sci 2021 Feb 17;22(4). Epub 2021 Feb 17.

Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS UMR 5089, 205 Route de Narbonne, 31077 Toulouse, France.

Bone metastasis remains the most frequent and the deadliest complication of prostate cancer (PCa). Mechanisms leading to the homing of tumor cells to bone remain poorly characterized. Role of chemokines in providing navigational cues to migrating cancer cells bearing specific receptors is well established. Bone is an adipocyte-rich organ since 50 to 70% of the adult bone marrow (BM) volume comprise bone marrow adipocytes (BM-Ads), which are likely to produce chemokines within the bone microenvironment. Using in vitro migration assays, we demonstrated that soluble factors released by primary BM-Ads are able to support the directed migration of PCa cells in a CCR3-dependent manner. In addition, we showed that CCL7, a chemokine previously involved in the CCR3-dependent migration of PCa cells outside of the prostate gland, is released by BM-Ads. These effects are amplified by obesity and ageing, two clinical conditions known to promote aggressive and metastatic PCa. In tumors, we found an enrichment of CCR3 in bone metastasis vs. primary tumors at mRNA levels using Oncomine microarray database. In addition, immunohistochemistry experiments demonstrated overexpression of CCR3 in bone versus visceral metastases. These results underline the potential importance of BM-Ads in the bone metastatic process and imply a CCR3/CCL7 axis whose pharmacological interest needs to be evaluated.
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http://dx.doi.org/10.3390/ijms22041994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922974PMC
February 2021

Antibody-based delivery of interleukin-9 to neovascular structures: Therapeutic evaluation in cancer and arthritis.

Exp Biol Med (Maywood) 2021 Apr 21;246(8):940-951. Epub 2021 Jan 21.

Philochem AG, Libernstrasse 3, Otelfingen 8112, Switzerland.

Interleukin-9 is a cytokine with multiple functions, including the ability to activate group 2 innate lymphoid cells, which has been postulated to be therapeutically active in mouse models of arthritis. Similarly, interleukin-9 has been suggested to play an important role in tumor immunity. Here, we describe the cloning, expression, and characterization of three fusion proteins based on murine interleukin-9 and the F8 antibody, specific to the alternatively spliced EDA domain of fibronectin. EDA is strongly expressed in cancer and in various arthritic conditions, while being undetectable in the majority of healthy organs. Interleukin-9-based fusion proteins with an irrelevant antibody specific to hen egg lysozyme served as negative control in our study. The fusion proteins were characterized by quantitative biodistribution analysis in tumor-bearing mice using radioiodinated protein preparations. The highest tumor uptake and best tumor:organ ratios were observed for a format, in which the interleukin-9 moiety was flanked by two units of the F8 antibody in single-chain Fv format. Biological activity of interleukin-9 was retained when the payload was fused to antibodies. However, the targeted delivery of interleukin-9 to the disease site resulted in a modest anti-tumor activity in three different murine models of cancer (K1735M2, CT26, and F9), while no therapeutic benefit was observed in a collagen induced model of arthritis. Collectively, these results confirm the possibility to deliver interleukin-9 to the site of disease but cast doubts about the alleged therapeutic activity of this cytokine in cancer and arthritis, which has been postulated in previous publications.
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http://dx.doi.org/10.1177/1535370220981578DOI Listing
April 2021

Postoperative Delirium is a Risk Factor of Poor Evolution Three Years After Cardiac Surgery: An Observational Cohort Study.

Clin Interv Aging 2020 18;15:2375-2381. Epub 2020 Dec 18.

Anesthesiology and Intensive Care Department, CHU Toulouse, Toulouse, France.

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; =0.006), metabolic status (diabetic patients; OR: 4; 95%CI: 1.6-10.2; =0.002), Euroscore 2 (Euroscore 2 >1.5; OR: 5.2; 95%CI: 1.7-15.4; =0.003) and POD (OR: 3.3; 95%CI 1.4-7.8; =0.006). Coronary disease was protective (OR: 0.3; 95%CI: 0.14-0.71; =0.006).

Conclusion: After cardiac surgery, POD significantly altered patient evolution and increased risk of dependence and loss of QOL.
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http://dx.doi.org/10.2147/CIA.S265797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755370PMC
December 2020

Obesity of mice lacking VAP-1/SSAO by Aoc3 gene deletion is reproduced in mice expressing a mutated vascular adhesion protein-1 (VAP-1) devoid of amine oxidase activity.

J Physiol Biochem 2021 Feb 25;77(1):141-154. Epub 2020 Jul 25.

Institute of Metabolic and Cardiovascular Diseases, INSERM, UMR1048, Toulouse, France.

The product of Aoc3 gene is known as vascular adhesion protein-1 (VAP-1), a glycoprotein contributing to leukocyte extravasation and exhibiting semicarbazide-sensitive amine oxidase activity (SSAO). Regarding the immune functions of VAP-1/SSAO, it is known that mice bearing Aoc3 gene knock-out (AOC3KO) exhibit defects in leukocyte migration similar to those of mice expressing a mutated VAP-1 lacking functional SSAO activity (knock-in, AOC3KI). However, it has not been reported whether these models differ regarding other disturbances. Thus, we further compared endocrine-metabolic phenotypes of AOC3KO and AOC3KI mice to their respective control. Special attention was paid on adiposity, glucose and lipid handling, since VAP-1/SSAO is highly expressed in adipose tissue (AT). In both mouse lines, no tissue SSAO activity was found, while Aoc3 mRNA was absent in AOC3KO only. Although food consumption was unchanged, both AOC3KO and AOC3KI mice were heavier and fatter than their respective controls. Other alterations commonly found in adipocytes from both lines were loss of benzylamine insulin-like action with unchanged insulin lipogenic responsiveness and adiponectin expression. A similar downregulation of inflammatory markers (CD45, IL6) was found in AT. Glucose handling and liver mass remained unchanged, while circulating lipid profile was distinctly altered, with increased cholesterol in AOC3KO only. These results suggest that the lack of oxidase activity found in AOC3KI is sufficient to reproduce the metabolic disturbances observed in AOC3KO mice, save those related with cholesterol transport. Modulation of SSAO activity therefore constitutes a potential target for the treatment of cardiometabolic diseases, especially obesity when complicated by low-grade inflammation.
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http://dx.doi.org/10.1007/s13105-020-00756-yDOI Listing
February 2021

Adipocyte Fatty Acid Transfer Supports Megakaryocyte Maturation.

Cell Rep 2020 07;32(1):107875

INSERM U1048 and Paul Sabatier University, Institute of Cardiovascular and Metabolic Diseases, Toulouse, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.celrep.2020.107875DOI Listing
July 2020

Macrophage-derived HMGB1 is dispensable for tissue fibrogenesis.

FASEB Bioadv 2019 Apr 12;1(4):227-245. Epub 2019 Feb 12.

Institut des Maladies Métaboliques et Cardiovasculaires, UMR 1048/I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse Toulouse France.

Alarmins and damage-associated molecular patterns (DAMPs) are powerful inflammatory mediators, capable of initiating and maintaining sterile inflammation during acute or chronic tissue injury. Recent evidence suggests that alarmins/DAMPs may also trigger tissue regeneration and repair, suggesting a potential contribution to tissue fibrogenesis. High mobility group B1 (HMGB1), a bona fide alarmin/DAMP, may be released passively by necrotic cells or actively secreted by innate immune cells. Macrophages can release large amounts of HMGB1 and play a key role in wound healing and regeneration processes. Here, we hypothesized that macrophages may be a key source of HMGB1 and thereby contribute to wound healing and fibrogenesis. Surprisingly, cell-specific deletion approaches, demonstrated that macrophage-derived HMGB1 is not involved in tissue fibrogenesis in multiple organs with different underlying pathologies. Compared to control HMGB1 mice, mice with macrophage-specific HMGB1 deletion (HMGB1) do not display any modification of fibrogenesis in the liver after CCL or thioacetamide treatment and bile duct ligation; in the kidney following unilateral ureter obstruction; and in the heart after transverse aortic constriction. Of note, even under thermoneutral housing, known to exacerbate inflammation and fibrosis features, HMGB1 mice do not show impairment of fibrogenesis. In conclusion, our study clearly establishes that macrophage-derived HMGB1 does not contribute to tissue repair and fibrogenesis.
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http://dx.doi.org/10.1096/fba.2018-00035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996376PMC
April 2019

Human Bone Marrow Is Comprised of Adipocytes with Specific Lipid Metabolism.

Cell Rep 2020 01;30(4):949-958.e6

Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France. Electronic address:

Under caloric restriction, bone marrow adipocytes (BM-Ads) do not decrease in size compared to white adipocytes, suggesting they harbor unique metabolic properties. We compare human primary BM-Ads with paired subcutaneous adipocytes (SC-Ads) using proteomic and lipidomic approaches. We find that, although SC-Ads and BM-Ads share similar morphological features, they possess distinct lipid metabolism. Although BM-Ad shows enrichment in proteins involved in cholesterol metabolism, correlating with increased free cholesterol content, proteins involved in lipolysis were downregulated. In particular, monoacylglycerol lipase expression is strongly reduced in BM-Ads, leading to monoacylglycerol accumulation. Consequently, basal and induced lipolytic responses are absent in BM-Ads, affirming their differences in metabolic fitness upon caloric restriction. These specific metabolic features are not recapitulated in vitro using common protocols to differentiate bone marrow mesenchymal stem cells. Thus, contrary to classical SC-Ads, BM-Ads display a specific lipid metabolism, as they are devoid of lipolytic activity and exhibit a cholesterol-orientated metabolism.
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http://dx.doi.org/10.1016/j.celrep.2019.12.089DOI Listing
January 2020

Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells.

EMBO J 2020 02 10;39(3):e102525. Epub 2020 Jan 10.

Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS, UPS, Université de Toulouse, Toulouse, France.

Extracellular vesicles are emerging key actors in adipocyte communication. Notably, small extracellular vesicles shed by adipocytes stimulate fatty acid oxidation and migration in melanoma cells and these effects are enhanced in obesity. However, the vesicular actors and cellular processes involved remain largely unknown. Here, we elucidate the mechanisms linking adipocyte extracellular vesicles to metabolic remodeling and cell migration. We show that adipocyte vesicles stimulate melanoma fatty acid oxidation by providing both enzymes and substrates. In obesity, the heightened effect of extracellular vesicles depends on increased transport of fatty acids, not fatty acid oxidation-related enzymes. These fatty acids, stored within lipid droplets in cancer cells, drive fatty acid oxidation upon being released by lipophagy. This increase in mitochondrial activity redistributes mitochondria to membrane protrusions of migrating cells, which is necessary to increase cell migration in the presence of adipocyte vesicles. Our results provide key insights into the role of extracellular vesicles in the metabolic cooperation that takes place between adipocytes and tumors with particular relevance to obesity.
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http://dx.doi.org/10.15252/embj.2019102525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996584PMC
February 2020

Plasma Apelin and Risk of Type 2 Diabetes in a Cohort From the Community.

Diabetes Care 2020 02 5;43(2):e15-e16. Epub 2019 Dec 5.

INSERM Research Unit 1138, Cordeliers Research Center, Sorbonne Université, Paris, France.

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http://dx.doi.org/10.2337/dc19-1865DOI Listing
February 2020

Catalytic dysregulation of SHP2 leading to Noonan syndromes affects platelet signaling and functions.

Blood 2019 12;134(25):2304-2317

Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048 and Université Paul Sabatier, Toulouse, France.

Src homology 2 domain-containing phosphatase 2 (SHP2), encoded by the PTPN11 gene, is a ubiquitous protein tyrosine phosphatase that is a critical regulator of signal transduction. Germ line mutations in the PTPN11 gene responsible for catalytic gain or loss of function of SHP2 cause 2 disorders with multiple organ defects: Noonan syndrome (NS) and NS with multiple lentigines (NSML), respectively. Bleeding anomalies have been frequently reported in NS, but causes remain unclear. This study investigates platelet activation in patients with NS and NSML and in 2 mouse models carrying PTPN11 mutations responsible for these 2 syndromes. Platelets from NS mice and patients displayed a significant reduction in aggregation induced by low concentrations of GPVI and CLEC-2 agonists and a decrease in thrombus growth on a collagen surface under arterial shear stress. This was associated with deficiencies in GPVI and αIIbβ3 integrin signaling, platelet secretion, and thromboxane A2 generation. Similarly, arterial thrombus formation was significantly reduced in response to a local carotid injury in NS mice, associated with a significant increase in tail bleeding time. In contrast, NSML mouse platelets exhibited increased platelet activation after GPVI and CLEC-2 stimulation and enhanced platelet thrombotic phenotype on collagen matrix under shear stress. Blood samples from NSML patients also showed a shear stress-dependent elevation of platelet responses on collagen matrix. This study brings new insights into the understanding of SHP2 function in platelets, points to new thrombopathies linked to platelet signaling defects, and provides important information for the medical care of patients with NS in situations involving risk of bleeding.
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http://dx.doi.org/10.1182/blood.2019001543DOI Listing
December 2019

Apelin affects the mouse aging urinary peptidome with minimal effects on kidney.

Sci Rep 2019 07 23;9(1):10647. Epub 2019 Jul 23.

Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.

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.
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http://dx.doi.org/10.1038/s41598-019-47109-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650410PMC
July 2019

Neuromedin U is a gut peptide that alters oral glucose tolerance by delaying gastric emptying via direct contraction of the pylorus and vagal-dependent mechanisms.

FASEB J 2019 04 12;33(4):5377-5388. Epub 2019 Feb 12.

Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 1149, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Diderot, Paris, France.

The gut-brain peptide neuromedin U (NMU) decreases food intake and body weight and improves glucose tolerance. Here, we characterized NMU as an enteropeptide and determined how it impacts glucose excursion. NMU was expressed predominantly in the proximal small intestine, and its secretion was triggered by ingestion of a mixed meal. Although a single peripheral injection of NMU in C57BL/6NRj mice prevented the rise of glycemia upon an oral but not an intraperitoneal load of glucose, it unexpectedly prevented insulin secretion, only slightly improved peripheral insulin sensitivity, and barely reduced intestinal glucose absorption. Interestingly, peripheral administration of NMU abrogated gastric emptying. NMU receptors 1 and 2 were detected in pyloric muscles and NMU was able to directly induce pyloric contraction in a dose-dependent manner ex vivo in isometric chambers. Using a modified glucose tolerance test, we demonstrate that improvement of oral glucose tolerance by NMU was essentially, if not exclusively, because of its impact on gastric emptying. Part of this effect was abolished in vagotomized (VagoX) mice, suggesting implication of the vagus tone. Accordingly, peripheral injection of NMU was associated with increased number of c-FOS-positive neurons in the nucleus of the solitary tract, which was partly prevented in VagoX mice. Finally, NMU kept its ability to improve oral glucose tolerance in obese and diabetic murine models. Together, these data demonstrate that NMU is an enteropeptide that prevents gastric emptying directly by triggering pylorus contraction and indirectly through vagal afferent neurons. This blockade consequently reduces intestinal nutrient absorption and thereby results in an apparent improved tolerance to oral glucose challenge.-Jarry, A.-C., Merah, N., Cisse, F., Cayetanot, F., Fiamma, M.-N., Willemetz, A., Gueddouri, D., Barka, B., Valet, P., Guilmeau, S., Bado, A., Le Beyec, J., Bodineau, L., Le Gall, M. Neuromedin U is a gut peptide that alters oral glucose tolerance by delaying gastric emptying via direct contraction of the pylorus and vagal-dependent mechanisms.
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http://dx.doi.org/10.1096/fj.201801718RDOI Listing
April 2019

Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP).

Breast Cancer Res 2019 01 17;21(1). Epub 2019 Jan 17.

Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, UMR 5089, 205 route de Narbonne, 31077, Toulouse, France.

Introduction: Clinical studies suggest that obesity, in addition to promoting breast cancer aggressiveness, is associated with a decrease in chemotherapy efficacy, although the mechanisms involved remain elusive. As chemotherapy is one of the main treatments for aggressive or metastatic breast cancer, we investigated whether adipocytes can mediate resistance to doxorubicin (DOX), one of the main drugs used to treat breast cancer, and the mechanisms associated.

Methods: We used a coculture system to grow breast cancer cells with in vitro differentiated adipocytes as well as primary mammary adipocytes isolated from lean and obese patients. Drug cellular accumulation, distribution, and efflux were studied by immunofluorescence, flow cytometry, and analysis of extracellular vesicles. Results were validated by immunohistochemistry in a series of lean and obese patients with cancer.

Results: Adipocytes differentiated in vitro promote DOX resistance (with cross-resistance to paclitaxel and 5-fluorouracil) in a large panel of human and murine breast cancer cell lines independently of their subtype. Subcellular distribution of DOX was altered in cocultivated cells with decreased nuclear accumulation of the drug associated with a localized accumulation in cytoplasmic vesicles, which then are expelled into the extracellular medium. The transport-associated major vault protein (MVP), whose expression was upregulated by adipocytes, mediated both processes. Coculture with human mammary adipocytes also induced chemoresistance in breast cancer cells (as well as the related MVP-induced DOX efflux) and their effect was amplified by obesity. Finally, in a series of human breast tumors, we observed a gradient of MVP expression, which was higher at the invasive front, where tumor cells are at close proximity to adipocytes, than in the tumor center, highlighting the clinical relevance of our results. High expression of MVP in these tumor cells is of particular interest since they are more likely to disseminate to give rise to chemoresistant metastases.

Conclusions: Collectively, our study shows that adipocytes induce an MVP-related multidrug-resistant phenotype in breast cancer cells, which could contribute to obesity-related chemoresistance.
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http://dx.doi.org/10.1186/s13058-018-1088-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337862PMC
January 2019

Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress.

Mol Cancer Res 2019 03 3;17(3):821-835. Epub 2019 Jan 3.

Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France.

Prostate gland is surrounded by periprostatic adipose tissue (PPAT), which is increasingly believed to play a paracrine role in prostate cancer progression. Our previous work demonstrates that adipocytes promote homing of prostate cancer cells to PPAT and that this effect is upregulated by obesity. Here, we show that once tumor cells have invaded PPAT (mimicked by an model of coculture), they establish a bidirectional crosstalk with adipocytes, which promotes tumor cell invasion. Indeed, tumor cells induce adipocyte lipolysis and the free fatty acids (FFA) released are taken up and stored by tumor cells. Incubation with exogenous lipids also stimulates tumor cell invasion, underlining the importance of lipid transfer in prostate cancer aggressiveness. Transferred FFAs (after coculture or exogenous lipid treatment) stimulate the expression of one isoform of the pro-oxidant enzyme NADPH oxidase, NOX5. NOX5 increases intracellular reactive oxygen species (ROS) that, in turn, activate a HIF1/MMP14 pathway, which is responsible for the increased tumor cell invasion. In obesity, tumor-surrounding adipocytes are more prone to activate the depicted signaling pathway and to induce tumor invasion. Finally, the expression of NOX5 and MMP14 is upregulated at the invasive front of human tumors where cancer cells are in close proximity to adipocytes and this process is amplified in obese patients, underlining the clinical relevance of our results. IMPLICATIONS: Our work emphasizes the key role of adjacent PPAT in prostate cancer dissemination and proposes new molecular targets for the treatment of obese patients exhibiting aggressive diseases.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0748DOI Listing
March 2019

The apelin/APJ system as a therapeutic target in metabolic diseases.

Expert Opin Ther Targets 2019 03 10;23(3):215-225. Epub 2019 Jan 10.

a Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM U1048 , Université de Toulouse , Toulouse , France.

Introduction: Apelin, a bioactive peptide, is the endogenous ligand of APJ, a G protein-coupled receptor which is widely expressed in peripheral tissues and in the central nervous system. The apelin/APJ system is involved in the regulation of various physiological functions and is a therapeutic target in different pathologies; the development of APJ agonists and antagonists has thus increased. Area covered: This review focuses on the in vitro and in vivo metabolic effects of apelin in physiological conditions and in the context of metabolic diseases. Expert opinion: In experimental models, novel APJ agonists are efficient in vivo, to treat metabolic diseases and associated complications. However, more clinical trials are necessary to determine whether molecules that target APJ could become an alternative therapeutic strategy in the treatment of metabolic diseases and associated complications.
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http://dx.doi.org/10.1080/14728222.2019.1561871DOI Listing
March 2019

Diet-induced obesity and associated disorders are prevented by natural bioactive type 1 fish collagen peptides (Naticol®) treatment.

J Physiol Biochem 2018 Nov 19;74(4):647-654. Epub 2018 Sep 19.

Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse, UPS, Toulouse, France.

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.
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http://dx.doi.org/10.1007/s13105-018-0650-0DOI Listing
November 2018

The exerkine apelin reverses age-associated sarcopenia.

Nat Med 2018 09 30;24(9):1360-1371. Epub 2018 Jul 30.

Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse, Université Paul Sabatier, Toulouse, France.

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.
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http://dx.doi.org/10.1038/s41591-018-0131-6DOI Listing
September 2018

Isoprostanes as markers for muscle aging in older athletes.

Biochim Open 2018 Jun 15;6:1-8. Epub 2017 Dec 15.

Institute of Metabolic and Cardiovascular Diseases, Joint Research Unit 1048 INSERM Adipolab Unit - Paul Sabatier University, Toulouse, France.

Introduction: Production of isoprostanes (IsoPs) is enhanced after acute, intense, and prolonged exercise, in untrained subjects. This effect is greater in older subjects. The present study aims to delineate the profile of acute-exercise-induced IsoPs levels in young and older endurance-trained subjects.

Methods: All included subjects were male, young (n = 6; 29 yrs ± 5.7) or older (n = 6; 63.7 yrs ± 2.3), and competitors. The kinetics of F-IsoPs in blood-sera was assessed at rest, for the maximal aerobic exercise power (MAP) corresponding to the cardio-respiratory fitness index and after a 30-min recovery period.

Results: No significant time effect on F-IsoPs kinetics was identified in young subjects. However, in older athletes, F-IsoPs blood-concentrations at the MAP were higher than at rest, whereas these blood-concentrations did not differ between rest and after the 30-min recovery period.

Conclusion: Because plasma glutathione (GSH) promotes the formation of some F-IsoPs, we suggest that the surprising decrease in F-IsoPs levels in older subjects would be caused by decreased GSH under major ROS production in older subjects. We argue that the assessment F-IsoPs in plasma as biomarkers of the aging process should be challenged by exercise to improve the assessment of the functional response against reactive oxygen species in older subjects.
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http://dx.doi.org/10.1016/j.biopen.2017.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991887PMC
June 2018

Esophageal cancer cells resistant to T-DM1 display alterations in cell adhesion and the prostaglandin pathway.

Oncotarget 2018 Apr 20;9(30):21141-21155. Epub 2018 Apr 20.

Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS 5286 University of Lyon, Lyon, France.

Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate that specifically targets HER2 thanks to its antibody component trastuzumab. In spite of responses to this novel agent, acquired resistance to treatment remains a major obstacle. Prolonged exposure of the gastroesophageal junction cancer cell line OE-19 to T-DM1, in the absence or presence of ciclosporin A resulted in the selection of two resistant cell lines to T-DM1. T-DM1-resistant cells presented an increased expression of adhesion genes, altered spreading and higher sensitivity to anoikis than parental cells. A resistant cell line showed decreased adhesion strength, increased migration speed and increased sensitivity to RhoA inhibition. Genes involved in the prostaglandin pathway were deregulated in resistant models. Addition of prostaglandin E to T-DM1 partially restored its cytotoxic activity in resistant models. This work demonstrates that T-DM1-resistance may be associated with alterations of cell adhesion and the prostaglandin pathway, which might constitute novel therapeutic targets.
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http://dx.doi.org/10.18632/oncotarget.24975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940380PMC
April 2018

Noonan syndrome-causing SHP2 mutants impair ERK-dependent chondrocyte differentiation during endochondral bone growth.

Hum Mol Genet 2018 07;27(13):2276-2289

INSERM UMR 1043, Centre of Pathophysiology of Toulouse Purpan (CPTP), University of Toulouse Paul Sabatier, Toulouse, France.

Growth retardation is a constant feature of Noonan syndrome (NS) but its physiopathology remains poorly understood. We previously reported that hyperactive NS-causing SHP2 mutants impair the systemic production of insulin-like growth factor 1 (IGF1) through hyperactivation of the RAS/extracellular signal-regulated kinases (ERK) signalling pathway. Besides endocrine defects, a direct effect of these mutants on growth plate has not been explored, although recent studies have revealed an important physiological role for SHP2 in endochondral bone growth. We demonstrated that growth plate length was reduced in NS mice, mostly due to a shortening of the hypertrophic zone and to a lesser extent of the proliferating zone. These histological features were correlated with decreased expression of early chondrocyte differentiation markers, and with reduced alkaline phosphatase staining and activity, in NS murine primary chondrocytes. Although IGF1 treatment improved growth of NS mice, it did not fully reverse growth plate abnormalities, notably the decreased hypertrophic zone. In contrast, we documented a role of RAS/ERK hyperactivation at the growth plate level since 1) NS-causing SHP2 mutants enhance RAS/ERK activation in chondrocytes in vivo (NS mice) and in vitro (ATDC5 cells) and 2) inhibition of RAS/ERK hyperactivation by U0126 treatment alleviated growth plate abnormalities and enhanced chondrocyte differentiation. Similar effects were obtained by chronic treatment of NS mice with statins. In conclusion, we demonstrated that hyperactive NS-causing SHP2 mutants impair chondrocyte differentiation during endochondral bone growth through a local hyperactivation of the RAS/ERK signalling pathway, and that statin treatment may be a possible therapeutic approach in NS.
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http://dx.doi.org/10.1093/hmg/ddy133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005060PMC
July 2018

Galanin enhances systemic glucose metabolism through enteric Nitric Oxide Synthase-expressed neurons.

Mol Metab 2018 04 31;10:100-108. Epub 2018 Jan 31.

Institut National de la Santé et de la Recherche Médicale (INSERM), U1220, Université Paul Sabatier, UPS, Institut de Recherche en Santé Digestive et Nutrition (IRSD), CHU Purpan, Place du Docteur Baylac, CS 60039, 31024 Toulouse Cedex 3, France; NeuroMicrobiota, European Associated Laboratory (EAL) INSERM/UCL, France. Electronic address:

Objective: Decreasing duodenal contraction is now considered as a major focus for the treatment of type 2 diabetes. Therefore, identifying bioactive molecules able to target the enteric nervous system, which controls the motility of intestinal smooth muscle cells, represents a new therapeutic avenue. For this reason, we chose to study the impact of oral galanin on this system in diabetic mice.

Methods: Enteric neurotransmission, duodenal contraction, glucose absorption, modification of gut-brain axis, and glucose metabolism (glucose tolerance, insulinemia, glucose entry in tissue, hepatic glucose metabolism) were assessed.

Results: We show that galanin, a neuropeptide expressed in the small intestine, decreases duodenal contraction by stimulating nitric oxide release from enteric neurons. This is associated with modification of hypothalamic nitric oxide release that favors glucose uptake in metabolic tissues such as skeletal muscle, liver, and adipose tissue. Oral chronic gavage with galanin in diabetic mice increases insulin sensitivity, which is associated with an improvement of several metabolic parameters such as glucose tolerance, fasting blood glucose, and insulin.

Conclusion: Here, we demonstrate that oral galanin administration improves glucose homeostasis via the enteric nervous system and could be considered a therapeutic potential for the treatment of T2D.
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http://dx.doi.org/10.1016/j.molmet.2018.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985240PMC
April 2018

Chronic apelin treatment improves hepatic lipid metabolism in obese and insulin-resistant mice by an indirect mechanism.

Endocrine 2018 04 1;60(1):112-121. Epub 2018 Feb 1.

Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France.

Purpose: Apelin treatment has been shown to improve insulin sensitivity in insulin resistant mice by acting in skeletal muscles. However, the effects of systemic apelin on the hepatic energy metabolism have not been addressed. We thus aimed to determine the effect of chronic apelin treatment on the hepatic lipid metabolism in insulin resistant mice. The apelin receptor (APJ) expression was also studied in this context since its regulation has only been reported in severe liver pathologies.

Methods: Mice were fed a high-fat diet (HFD) in order to become obese and insulin resistant compared to chow fed mice (CD). HFD mice then received a daily intraperitoneal injection of apelin (0.1 µmol/kg) or PBS during 28 days.

Results: Triglycerides content and the expression of different lipogenesis-related genes were significantly decreased in the liver of HFD apelin-treated compared to PBS-treated mice. Moreover, at this stage of insulin resistance, the beta-oxidation was increased in liver homogenates of HFD PBS-treated mice compared to CD mice and reduced in HFD apelin-treated mice. Finally, APJ expression was not up-regulated in the liver of insulin resistant mice. In isolated hepatocytes from chow and HFD fed mice, apelin did not induce significant effect.

Conclusions: Altogether, these results suggest that systemic apelin treatment decreases steatosis in insulin resistant mice without directly targeting hepatocytes.
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http://dx.doi.org/10.1007/s12020-018-1536-1DOI Listing
April 2018

Therapeutic Benefit and Gene Network Regulation by Combined Gene Transfer of Apelin, FGF2, and SERCA2a into Ischemic Heart.

Mol Ther 2018 03 16;26(3):902-916. Epub 2017 Nov 16.

UMR 1048-I2MC, Université de Toulouse, INSERM, FHU IMPACT, 31432 Toulouse, France. Electronic address:

Despite considerable advances in cardiovascular disease treatment, heart failure remains a public health challenge. In this context, gene therapy appears as an attractive approach, but clinical trials using single therapeutic molecules result in moderate benefit. With the objective of improving ischemic heart failure therapy, we designed a combined treatment, aimed to simultaneously stimulate angiogenesis, prevent cardiac remodeling, and restore contractile function. We have previously validated IRES-based vectors as powerful tools to co-express genes of interest. Mono- and multicistronic lentivectors expressing fibroblast growth factor 2 (angiogenesis), apelin (cardioprotection), and/or SERCA2a (contractile function) were produced and administrated by intramyocardial injection into a mouse model of myocardial infarction. Data reveal that combined treatment simultaneously improves vessel number, heart function parameters, and fibrosis prevention, due to FGF2, SERCA2a, and apelin, respectively. Furthermore, addition of SERCA2a in the combination decreases cardiomyocyte hypertrophy. Large-scale transcriptome analysis reveals that the triple treatment is the most efficient in restoring angiogenic balance as well as expression of genes involved in cardiac function and remodeling. Our study validates the concept of combined treatment of ischemic heart disease with apelin, FGF2, and SERCA2a and shows that such therapeutic benefit is mediated by a more effective recovery of gene network regulation.
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http://dx.doi.org/10.1016/j.ymthe.2017.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910659PMC
March 2018

Pharmacological targeting of apelin impairs glioblastoma growth.

Brain 2017 Nov;140(11):2939-2954

CRCINA, Inserm, Team SOAP, CNRS, Universite de Nantes, Nantes, France.

Glioblastoma are highly aggressive brain tumours that are associated with an extremely poor prognosis. Within these tumours exists a subpopulation of highly plastic self-renewing cancer cells that retain the ability to expand ex vivo as tumourspheres, induce tumour growth in mice, and have been implicated in radio- and chemo-resistance. Although their identity and fate are regulated by external cues emanating from endothelial cells, the nature of such signals remains unknown. Here, we used a mass spectrometry proteomic approach to characterize the factors released by brain endothelial cells. We report the identification of the vasoactive peptide apelin as a central regulator for endothelial-mediated maintenance of glioblastoma patient-derived cells with stem-like properties. Genetic and pharmacological targeting of apelin cognate receptor abrogates apelin- and endothelial-mediated expansion of glioblastoma patient-derived cells with stem-like properties in vitro and suppresses tumour growth in vivo. Functionally, selective competitive antagonists of apelin receptor were shown to be safe and effective in reducing tumour expansion and lengthening the survival of intracranially xenografted mice. Therefore, the apelin/apelin receptor signalling nexus may operate as a paracrine signal that sustains tumour cell expansion and progression, suggesting that apelin is a druggable factor in glioblastoma.
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http://dx.doi.org/10.1093/brain/awx253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841205PMC
November 2017

Apelin administration improves insulin sensitivity in overweight men during hyperinsulinaemic-euglycaemic clamp.

Diabetes Obes Metab 2018 01 10;20(1):157-164. Epub 2017 Aug 10.

Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse, UPS, Toulouse, France.

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 2 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 2 hyperinsulinaemic-euglycaemic clamps where the basal level of glucose infusion rate (GIR) was measured from the 90th to the 120th minute (level 1). Continuous intravenous administration of apelin or placebo was ongoing for 2 hours and GIR was finally evaluated from the 210th to the 240th minute (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 = .055) whereas the highest dose significantly improved insulin sensitivity (0.82 ± 0.71 mg/kg/min, P = .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 studies in rodents, 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.
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http://dx.doi.org/10.1111/dom.13055DOI Listing
January 2018

Apelin modulates pathological remodeling of lymphatic endothelium after myocardial infarction.

JCI Insight 2017 Jun 15;2(12). Epub 2017 Jun 15.

I2MC INSERM UMR 1048, Toulouse Cedex, France.

Lymphatic endothelium serves as a barrier to control fluid balance and immune cell trafficking to maintain tissue homeostasis. Long-term alteration of lymphatic vasculature promotes edema and fibrosis, which is an aggravating factor in the onset of cardiovascular diseases such as myocardial infarction. Apelin is a bioactive peptide that plays a central role in angiogenesis and cardiac contractility. Despite an established role of apelin in lymphangiogenesis, little is known about its function in the cardiac lymphatic endothelium. Here, we show that apelin and its receptor APJ were exclusively expressed on newly formed lymphatic vasculature in a pathological model of myocardial infarction. Using an apelin-knockout mouse model, we identified morphological and functional defects in lymphatic vasculature associated with a proinflammatory status. Surprisingly, apelin deficiency increased the expression of lymphangiogenic growth factors VEGF-C and VEGF-D and exacerbated lymphangiogenesis after myocardial infarction. Conversely, the overexpression of apelin in ischemic heart was sufficient to restore a functional lymphatic vasculature and to reduce matrix remodeling and inflammation. In vitro, the expression of apelin prevented the alteration of cellular junctions in lymphatic endothelial cells induced by hypoxia. In addition, we demonstrated that apelin controls the secretion of the lipid mediator sphingosine-1-phosphate in lymphatic endothelial cells by regulating the level of expression of sphingosine kinase 2 and the transporter SPNS2. Taken together, our results show that apelin plays a key role in lymphatic vessel maturation and stability in pathological settings. Thus, apelin may represent a novel candidate to prevent pathological lymphatic remodeling in diseases.
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http://dx.doi.org/10.1172/jci.insight.93887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470877PMC
June 2017

A biomimetic hydrogel functionalized with adipose ECM components as a microenvironment for the 3D culture of human and murine adipocytes.

Biotechnol Bioeng 2017 08 8;114(8):1813-1824. Epub 2017 May 8.

CELENYS, Biopolis 2, 75 route de Lyons-la-forêt, Rouen 76000, France.

The lack of relevant in vitro models for adipose tissue makes necessary the development of a more physiological environment providing spatial and chemical cues for the effective maturation of adipocytes. We developed a biofunctionalized hydrogel with components of adipose extracellular matrix: collagen I, collagen VI, and the cell binding domain of fibronectin and we compared it to usual 2D cultures on plastic plates. This scaffold allowed 3D culture of mature adipocytes from the preadipocytes cell lines 3T3-L1 and 3T3-F442A, as well as primary Human White Preadipocytes (HWP), acquiring in vivo-like organization, with spheroid shaped adipocytes forming multicellular aggregates. The size of these aggregates increased with time up to 120 μm in diameter after 4 weeks of maturation, with good viability. Significantly higher lipogenic activity (up to 20-fold at day 28 for HWP cultures) and differentiation rates were also observed compared to 2D. Gene expression analyses highlighted earlier differentiation and complete maturation of 3D HWP compared to 2D, reinforced by the expression of Perilipin protein after 21 days of nutrition. This increase in adipocytes phenotypic and genotypic markers made this scaffold-driven culture as a robust adipose 3D model. Retinoic acid inhibition of lipogenesis in HWP or isoprenalin and caffeine induction of lipolysis performed on mouse 3T3-F442A cells, showed higher doses of molecules than typically used in 2D, underlying the physiologic relevance of this 3D culture system. Biotechnol. Bioeng. 2017;114: 1813-1824. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/bit.26306DOI Listing
August 2017

Inhibition of PIKfyve prevents myocardial apoptosis and hypertrophy through activation of SIRT3 in obese mice.

EMBO Mol Med 2017 06;9(6):770-785

INSERM U1048 I2MC, Toulouse, Cedex 4, France

PIKfyve is an evolutionarily conserved lipid kinase that regulates pleiotropic cellular functions. Here, we identify PIKfyve as a key regulator of cardiometabolic status and mitochondrial integrity in chronic diet-induced obesity. , we show that PIKfyve is critical for the control of mitochondrial fragmentation and hypertrophic and apoptotic responses to stress. We also provide evidence that inactivation of PIKfyve by the selective inhibitor STA suppresses excessive mitochondrial ROS production and apoptosis through a SIRT3-dependent pathway in cardiomyoblasts. In addition, we report that chronic STA treatment improves cardiometabolic profile in a mouse model of cardiomyopathy linked to obesity. We provide evidence that PIKfyve inhibition reverses obesity-induced cardiac mitochondrial damage and apoptosis by activating SIRT3. Furthermore, treatment of obese mice with STA improves left ventricular function and attenuates cardiac hypertrophy. In contrast, STA is not able to reduce isoproterenol-induced cardiac hypertrophy in SIRT3.KO mice. Altogether, these results unravel a novel role for PIKfyve in obesity-associated cardiomyopathy and provide a promising therapeutic strategy to combat cardiometabolic complications in obesity.
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http://dx.doi.org/10.15252/emmm.201607096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452048PMC
June 2017

Improvement of cardiometabolic markers after fish oil intervention in young Mexican adults and the role of PPARα L162V and PPARγ2 P12A.

J Nutr Biochem 2017 05 10;43:98-106. Epub 2017 Feb 10.

Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico. Electronic address:

Polyunsaturated fatty acids (PUFA) contained in fish oil (FO) are ligands for peroxisome proliferator-activated receptors (PPAR) that may induce changes in cardiometabolic markers. Variation in PPAR genes may influence the beneficial responses linked to FO supplementation in young adults. The study aimed to analyze the effect of FO supplementation on glucose metabolism, circulating lipids and inflammation according to PPARα L162V and PPARγ2 P12A genotypes in young Mexican adults. 191 young, non-smoking subjects between 18 and 40 years were included in a one-arm study. Participants were supplemented with 2.7 g/day of EPA+DHA, during six weeks. Dietary analysis, body composition measurements and indicators for glucose metabolism, circulating lipids, and markers for inflammation were analyzed before and after intervention. An overall decrease in triglycerides (TG) and an increase in HS-ω3 index were observed in all subjects [-4.1 mg/dL, (SD:±51.7), P=.02 and 2.6%, (SD:±1.2), P<.001 respectively]. Mean fasting insulin and glycated hemoglobin (HbA1c%) were significantly decreased in all subjects [-0.547mlU/L, (SD:±10.29), P=.034 and-0.07%, (SD:±0.3), P<.001 respectively], whereas there was no change in body composition, fasting glucose, adiponectin and inflammatory markers. Subjects carrying the minor alleles of PPARα L162V and PPARγ2 P12A had higher responses in reduction of TG and fasting insulin respectively. Interestingly, doses below 2.7 g/day (1.8 g/day) were sufficient to induce a significant reduction in fasting insulin and HbA1c% from baseline (P=.019 and P<.001). The observed responses in triglycerides and fasting insulin in the Mexican population give further evidence of the importance of FO supplementation in young people as an early step towards the prevention of cardiometabolic disease.
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http://dx.doi.org/10.1016/j.jnutbio.2017.02.002DOI Listing
May 2017

Protamine is an antagonist of apelin receptor, and its activity is reversed by heparin.

FASEB J 2017 06 27;31(6):2507-2519. Epub 2017 Feb 27.

Institut des Maladies Métaboliques et Cardiovasculaires, INSERM Unité 1048, Université de Toulouse, Université Paul Sabatier, Toulouse, France;

Apelin signaling plays an important role during embryo development and regulates angiogenesis, cardiovascular activity, and energy metabolism in adulthood. Overexpression and hyperactivity of this signaling pathway is observed in various pathologic states, such as cardiovascular diseases and cancer, which highlights the importance of inhibiting apelin receptor (APJ); therefore, we developed a cell-based screening assay that uses fluorescence microscopy to identify APJ antagonists. This approach led us to identify the U.S. Food and Drug Administration-approved compound protamine-already used clinically after cardiac surgery-as an agent to bind to heparin and thereby reverse its anticlotting activity. Protamine displays a 390-nM affinity for APJ and behaves as a full antagonist with regard to G protein and β-arrestin-dependent intracellular signaling. and , protamine abolishes well-known apelin effects, such as angiogenesis, glucose tolerance, and vasodilatation. Remarkably, protamine antagonist activity is fully reversed by heparin treatment both and Thus, our results demonstrate a new pharmacologic property of protamine-blockade of APJ-that could explain some adverse effects observed in protamine-treated patients. Moreover, our data reveal that the established antiangiogenic activity of protamine would rely on APJ antagonism.-Le Gonidec, S., Chaves-Almagro, C., Bai, Y., Kang, H. J., Smith, A., Wanecq, E., Huang, X.-P., Prats, H., Knibiehler, B., Roth, B. L., Barak, L. S., Caron, M. G., Valet, P., Audigier, Y., Masri, B. Protamine is an antagonist of apelin receptor, and its activity is reversed by heparin.
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http://dx.doi.org/10.1096/fj.201601074RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191096PMC
June 2017