AAV-mediated AP-1 decoy oligonucleotide expression inhibits aortic elastolysis in a mouse model of Marfan syndrome

2021 ◽  
Author(s):  
Anca Remes ◽  
Rawa Arif ◽  
Maximilian Franz ◽  
Andreas Jungmann ◽  
Marcin Zaradzki ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Ex Vivo ◽  
Binding Activity ◽  
Aortic Tissue ◽  
Inherited Disorders ◽  
Monocyte Chemoattractant Protein 1 ◽  
Fibrillin 1 ◽  
Decoy Oligonucleotide ◽  
Expression And Activity

Abstract Aims Marfan syndrome is one of the most common inherited disorders of connective tissue caused by fibrillin-1 mutations, characterized by enhanced transcription factor AP-1 DNA binding activity and subsequently abnormally increased expression and activity of matrix-metalloproteinases (MMPs). We aimed to establish a novel adeno-associated virus (AAV)-based strategy for long-term expression of an AP-1 neutralizing RNA hairpin (hp) decoy oligonucleotide (dON) in the aorta to prevent aortic elastolysis in a murine model of Marfan syndrome. Methods and results Using fibrillin-1 hypomorphic mice (mgR/mgR), aortic grafts from young (9 weeks old) donor mgR/mgR mice were transduced ex vivo with AAV vectors and implanted as infrarenal aortic interposition grafts in mgR/mgR mice. Grafts were explanted after 30 days. For in vitro studies, isolated primary aortic smooth muscle cells (SMCs) from mgR/mgR mice were used. Elastica-van-Giesson staining visualized elastolysis, reactive oxygen species (ROS) production was assessed using dihydroethidine staining. RNA F.I.S.H. verified AP-1 hp dON generation in the ex vivo transduced aortic tissue. MMP expression and activity were assessed by western blotting and immunoprecipitation combined with zymography. Transduction resulted in stable therapeutic dON expression in endothelial and SMCs. MMP expression and activity, ROS formation as well as expression of monocyte chemoattractant protein-1 were significantly reduced. Monocyte graft infiltration declined and the integrity of the elastin architecture was maintained. RNAseq analysis confirmed the beneficial effect of AP-1 neutralization on the pro-inflammatory environment in SMCs. Conclusion This novel approach protects from deterioration of aortic stability by sustained delivery of nucleic acids-based therapeutics and further elucidated how to interfere with the mechanism of elastolysis.

Abstract 16789: Loss of Endothelial Barrier in Fibrillin-1-Deficient Marfan Mice (mgR/mgR) Results in Severe Inflammation After Adenoviral Gene Therapy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Philipp C Seppelt ◽  
Simon Schwill ◽  
Rawa Arif ◽  
Antje Weber ◽  
Marcin Zaradzki ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Marfan Syndrome ◽  
Ex Vivo ◽  
Endothelial Barrier ◽  
Aortic Tissue ◽  
Tem Analysis ◽  
Adenoviral Gene Transfer ◽  
Severe Inflammation ◽  
Fibrillin 1 ◽  
Adenoviral Gene Therapy

Introduction: Nowadays surgery still remains option of choice for therapy of aneurysm in Marfan syndrome. Aortic tissue of Marfan patients shows elastolysis enhanced by proteolytic activity of Matrix Metalloproteinases (MMPs). In this study we performed adenoviral gene transfer of Tissue Inhibitor of MMP-1 (TIMP-1) in aortic grafts of Fibrillin-1-deficient Marfan mice (mgR/mgR) in order to reduce aortic elastolysis. Methods: We performed heterotopic infrarenal transplantation of thoracic aorta in female mice (n=35, n=7/group). MgR/mgR and wild-type (WT) aorta (C57BL/6) was either incubated ex vivo with adenoviral vector coding for human TIMP-1 or ß-Galactosidase (5x10^9pfu/ml) or as control with culture medium. 30 days after surgery overexpression of transgene was assessed by immunohistochemistry (IHC) and collagen in situ zymography (ISZ). Histologic staining was performed to outline elastin breaks, signs of inflammation and Neointimal Index (NI). Endothelial barrier was evaluated with the use of transmission electron microscope (TEM) and perfusion of fluorescent albumin. Results: IHC and ISZ revealed sufficient expression of transgene. Severe intimal hyperplasia and distinctive signs of cellular inflammation were solely observed in mgR/mgR aorta after adenoviral transduction (NI: ß-Gal 0.23; TIMP-1 0.43), but not in WT aorta (NI: Native 0.01; TIMP-1 0.00). Compared to native mgR/mgR and TIMP-1 treated WT aorta, NI in TIMP-1 treated mgR/mgR aorta was highly significantly larger (p=0.001; p=0.001). Native mgR/mgR grafts presented with severe elastolysis compared to WT (p=0.001). Regardless of the vector transduced elastolysis in mgR/mgR aorta after adenoviral gene therapy was more pronounced compared to WT aorta (ß-Gal p=0.001; TIMP-1 p=0.001). Albumin diffusion through the endothelial barrier was increased in native mgR/mgR aorta compared to native WT aorta (p=0.037). TEM analysis of mgR/mgR aorta displayed reconstruction of the basement membrane and basolateral space. Conclusions: Murine Marfan aortic grafts developed severe inflammation after adenoviral exposure. Fibrillin-1-deficiency is associated with dysfunction of endothelial barrier which could be a target for alternative therapies in Marfan syndrome.

scholarly journals Amyloid-Targeting PET Tracer [18F]Flutemetamol Accumulates in Atherosclerotic Plaques

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1072 ◽  
Author(s):  
Sanna Hellberg ◽  
Johanna Silvola ◽  
Heidi Liljenbäck ◽  
Max Kiugel ◽  
Olli Eskola ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Mouse Strains ◽  
Aortic Tissue ◽  
Atherosclerotic Plaques ◽  
Carotid Artery Plaque ◽  
Pet Tracer ◽  
Pet Ct ◽  
Human Carotid

Atherosclerosis is characterized by the accumulation of oxidized lipids in the artery wall, which triggers an inflammatory response. Oxidized low-density lipoprotein (ox-LDL) presents amyloid-like structural properties, and different amyloid species have recently been recognized in atherosclerotic plaques. Therefore, we studied the uptake of the amyloid imaging agent [18F]Flutemetamol in atherosclerotic plaques. The binding of [18F]Flutemetamol to human carotid artery plaque was studied in vitro. In vivo uptake of the tracer was studied in hypercholesterolemic IGF-II/LDLR−/−ApoB100/100 mice and C57BL/6N controls. Tracer biodistribution was studied in vivo with PET/CT, and ex vivo by gamma counter and digital ex vivo autoradiography. The presence of amyloid, ox-LDL, and macrophages in the plaques was examined by immunohistochemistry. [18F]Flutemetamol showed specific accumulation in human carotid plaque, especially in areas positive for amyloid beta. The aortas of IGF-II/LDLR−/−ApoB100/100 mice showed large thioflavin-S-positive atherosclerotic plaques containing ox-LDL and macrophages. Autoradiography revealed 1.7-fold higher uptake in the plaques than in a lesion-free vessel wall, but no difference in aortic tissue uptake between mouse strains were observed in the in vivo PET/CT. In conclusion, [18F]Flutemetamol binds to amyloid-positive areas in human atherosclerotic plaques. Further studies are warranted to clarify the uptake mechanisms, and the potential of the tracer for in vivo imaging of atherosclerosis in patients.

Abstract 103: Circulating sRAGE is Elevated in Patients with Marfan Syndrome and Decreases After Surgical Replacement of Diseased Aortic Segments

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Eric K Lai ◽  
Daniel J Wytowich ◽  
Giovanni Ferrari ◽  
Joseph E Bavaria ◽  
Reed E Pyeritz ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Marfan Syndrome ◽  
Aortic Surgery ◽  
Clinical Information ◽  
Aortic Disease ◽  
Aortic Diameter ◽  
Aortic Tissue ◽  
Post Surgery ◽  
Fibrillin 1 ◽  
One Year

Backgound: The Receptor for Advanced Glycation End products (RAGE) and its ligands are associated with vascular remodeling and trigger the release of a soluble receptor (sRAGE). We previously demonstrated that sRAGE levels are elevated in patients with bicuspid aortic valve and ascending aortic aneurysm. Circulating sRAGE in these patients correlates with the presence of a dysfunctional aortic structure but do not linearly correlate with an increase in the aortic diameter. Severe aortic disease occurs in more than 80% of Marfan Syndrome (MFS) patients. Aortic root and ascending aorta (AA) enlargement in MFS are associated with deficiency/destabilization of fibrillin-1, which leads to a generalized structural impairment of the aortic wall. We hypothesized that sRAGE may be elevated in the plasma of MFS patients and may decrease after surgical replacement of diseased aortic tissue. Methods: Plasma samples and clinical information (MFS=120, Control=37) were obtained from the GenTAC bioregistry and the Tissue Biobank at UPENN. Samples were collected either a few days prior to aortic surgery or at least one year post-surgery. sRAGE was tested using ELISA. Univariate and multivariate analysis were performed. Results: sRAGE levels are significantly higher in MFS patients compared to control (1404±64.35 vs 592±34.86 pg/ml, p<0.001) and are associated with the presence of MFS, independent of age, gender and comorbidities (p<0.001). sRAGE levels are significantly higher in MFS patients undergoing aortic surgery when compared to MFS patients monitored for aortic disease (1485±116.8 vs 1209±82.63 pg/ml, p=0.05). Circulating sRAGE is significantly lower in patients who have received aortic surgery (1185±63.31 pg/ml, p=0.02) and even lower in patients who received more extensive replacement (aortic valve/root and AA) versus those who underwent only aortic valve and root replacement (1313±81.83 vs 963.5±92.54 pg/ml, p=0.008). sRAGE levels do not linearly correlate with root and/or AA diameter. Conclusion: Plasma sRAGE levels are associated with the presence of ascending aortopathies independent of aortic diameter. Longitudinal studies evaluating sRAGE in MFS patients may unveil new markers for the diagnosis and risk stratification of this population.

scholarly journals Spontaneous Right Ventricular Pseudoaneurysms and Increased Arrhythmogenicity in a Mouse Model of Marfan Syndrome

2020 ◽  
Vol 21 (19) ◽  
pp. 7024
Author(s):  
Felke Steijns ◽  
Marjolijn Renard ◽  
Marine Vanhomwegen ◽  
Petra Vermassen ◽  
Jana Desloovere ◽  
...  
Keyword(s):  
Mouse Model ◽  
Right Ventricular ◽  
Marfan Syndrome ◽  
Matrix Protein ◽  
Ex Vivo ◽  
Wide Spectrum ◽  
Extracellular Matrix Protein ◽  
Aortic Dilatation ◽  
Cardiac Phenotype ◽  
Fibrillin 1

Patients with Marfan syndrome (MFS), a connective tissue disorder caused by pathogenic variants in the gene encoding the extracellular matrix protein fibrillin-1, have an increased prevalence of primary cardiomyopathy, arrhythmias, and sudden cardiac death. We have performed an in-depth in vivo and ex vivo study of the cardiac phenotype of Fbn1mgR/mgR mice, an established mouse model of MFS with a severely reduced expression of fibrillin-1. Using ultrasound measurements, we confirmed the presence of aortic dilatation and observed cardiac diastolic dysfunction in male Fbn1mgR/mgR mice. Upon post-mortem examination, we discovered that the mutant mice consistently presented myocardial lesions at the level of the right ventricular free wall, which we characterized as spontaneous pseudoaneurysms. Histological investigation demonstrated a decrease in myocardial compaction in the MFS mouse model. Furthermore, continuous 24 h electrocardiographic analysis showed a decreased heart rate variability and an increased prevalence of extrasystolic arrhythmic events in Fbn1mgR/mgR mice compared to wild-type littermates. Taken together, in this paper we document a previously unreported cardiac phenotype in the Fbn1mgR/mgR MFS mouse model and provide a detailed characterization of the cardiac dysfunction and rhythm disorders which are caused by fibrillin-1 deficiency. These findings highlight the wide spectrum of cardiac manifestations of MFS, which might have implications for patient care.

scholarly journals Long-Term Treatment of Azathioprine in Rats Induces Vessel Mineralization

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 327
Author(s):  
Mirjam Schuchardt ◽  
Jaqueline Herrmann ◽  
Cornelia Henkel ◽  
Milen Babic ◽  
Markus van der Giet ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Calcium Content ◽  
Immunosuppressive Drugs ◽  
Term Treatment ◽  
Aortic Tissue ◽  
Long Term Treatment ◽  
Vessel Structure ◽  
Vascular Stiffening

Medial vascular calcification (mVC) is closely related to cardiovascular disease, especially in patients suffering from chronic kidney disease (CKD). Even after successful kidney transplantation, cardiovascular mortality remains increased. There is evidence that immunosuppressive drugs might influence pathophysiological mechanisms in the vessel wall. Previously, we have shown in vitro that mVC is induced in vascular smooth muscle cells (VSMCs) upon treatment with azathioprine (AZA). This effect was confirmed in the current study in an in vivo rat model treated with AZA for 24 weeks. The calcium content increased in the aortic tissue upon AZA treatment. The pathophysiologic mechanisms involve AZA catabolism to 6-thiouracil via xanthine oxidase (XO) with subsequent induction of oxidative stress. Proinflammatory cytokines, such as interleukin (IL)-1ß and IL-6, increase upon AZA treatment, both systemically and in the aortic tissue. Further, VSMCs show an increased expression of core-binding factor α-1, alkaline phosphatase and osteopontin. As the AZA effect could be decreased in NLRP3−/− aortic rings in an ex vivo experiment, the signaling pathway might be, at least in part, dependent on the NLRP3 inflammasome. Although human studies are necessary to confirm the harmful effects of AZA on vascular stiffening, these results provide further evidence of induction of VSMC calcification under AZA treatment and its effects on vessel structure.

Platelet and endothelial activation in catastrophic and quiescent antiphospholipid syndrome

2013 ◽  
Vol 109 (05) ◽  
pp. 901-908 ◽  
Author(s):  
Agnese Bontadi ◽  
Emanuela Falcinelli ◽  
Silvia Giannini ◽  
Alessandro Marturano ◽  
Marta Tonello ◽  
...  
Keyword(s):  
Antiphospholipid Syndrome ◽  
Ex Vivo ◽  
Endothelial Activation ◽  
Monocyte Chemoattractant Protein 1 ◽  
Glycoprotein I ◽  
In Vitro Effects ◽  
Von Willebrand ◽  
Cell Adhesion Molecule 1 ◽  
Willebrand Factor

SummaryAntiphospholipid antibodies (aPL) seem to induce a prothrombotic state by activating endothelium and platelets, but no studies have evaluated systematically the effects of aPL from patients with the antiphospholipid syndrome (APS) in quiescent versus catastrophic phase. Our aims were to evaluate the in vitro effects on platelet activation of anti-β2 glycoprotein I (anti-β2GPI) antibodies isolated from APS patient in either quiescent or catastrophic phase and to investigate ex vivo platelet and endothelial activation in patients with quiescent or catastrophic APS. Anti-β2GPI antibodies were isolated from plasma of a pregnant woman in two different stages of APS (quiescent and catastrophic, respectively). They were co-incubated with washed platelets from healthy controls that were then challenged with TRAP-6 (thrombin receptor activating peptide 6) and the expression of P-selectin (P-sel) on platelets was assessed by flow cytometry. Moreover, plasma samples from six patients with quiescent, four with catastrophic APS and 10 controls were assessed for several markers of platelet and endothelial activation. The results showed that purified anti-β2GPI antibodies co-incubated with platelets enhanced TRAP-6-induced platelet P-sel expression. Notably, anti-β2GPI antibodies isolated during the catastrophic phase enhanced platelet P-sel expression more than antibodies isolated from the same patient in the quiescent stage of disease. Moreover, APS patients had significantly higher plasma levels of soluble (s) Psel, sCD40 ligand, soluble vascular cell adhesion molecule 1 and monocyte chemoattractant protein 1 than control subjects. In addition, sP-sel and von Willebrand factor activity were significantly higher during catastrophic than in quiescent phase.

scholarly journals Cyclophilin A/EMMPRIN Axis Is Involved in Pro-Fibrotic Processes Associated with Thoracic Aortic Aneurysm of Marfan Syndrome Patients

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 154 ◽  
Author(s):  
Gianluca L. Perrucci ◽  
Erica Rurali ◽  
Maria Corlianò ◽  
Maria Balzo ◽  
Michela Piccoli ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Marfan Syndrome ◽  
Thoracic Aortic Aneurysm ◽  
Cyclophilin A ◽  
Aortic Tissue ◽  
Tissue Samples ◽  
Abdominal Aortic ◽  
Tgf Β1 ◽  
In Vitro Treatment

Background: Marfan syndrome (MFS) is a genetic disease, characterized by thoracic aortic aneurysm (TAA), which treatment is to date purely surgical. Understanding of novel molecular targets is mandatory to unveil effective pharmacological approaches. Cyclophilin A (CyPA) and its receptor EMMPRIN are associated with several cardiovascular diseases, including abdominal aortic aneurysm. Here, we envisioned the contribution of CyPA/EMMPRIN axis in MFS-related TAA. Methods: We obtained thoracic aortic samples from healthy controls (HC) and MFS patients’ aortas and then isolated vascular smooth muscle cells (VSMC) from the aortic wall. Results: our findings revealed that MFS aortic tissue samples isolated from the dilated zone of aorta showed higher expression levels of EMMPRIN vs. MFS non-dilated aorta and HC. Interestingly, angiotensin II significantly stimulated CyPA secretion in MFS-derived VSMC (MFS-VSMC). CyPA treatment on MFS-VSMC led to increased levels of EMMPRIN and other MFS-associated pro-fibrotic mediators, such as TGF-β1 and collagen I. These molecules were downregulated by in vitro treatment with CyPA inhibitor MM284. Our results suggest that CyPA/EMMPRIN axis is involved in MFS-related TAA development, since EMMPRIN is upregulated in the dilated zone of MFS patients’ TAA and the inhibition of its ligand, CyPA, downregulated EMMPRIN and MFS-related markers in MFS-VSMC. Conclusions: these insights suggest both a novel detrimental role for CyPA/EMMPRIN axis and its inhibition as a potential therapeutic strategy for MFS-related TAA treatment.

scholarly journals 2027 The role of lysyl oxidase in systemic sclerosis-associated lung fibrosis

2018 ◽  
Vol 2 (S1) ◽  
pp. 32-33
Author(s):  
Xinh-Xinh Nguyen ◽  
Tetsuya Nishimoto ◽  
Takahisa Takihara ◽  
Logan Mlakar ◽  
Ellen Riemer ◽  
...  
Keyword(s):  
Lung Fibrosis ◽  
Human Lung ◽  
Ex Vivo ◽  
Lysyl Oxidase ◽  
Lung Fibroblasts ◽  
Primary Fibroblasts ◽  
Expression And Activity

OBJECTIVES/SPECIFIC AIMS: Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology characterized by progressive fibrosis of the skin and multiple visceral organs. Effective therapies for SSc are needed. Lysyl oxidase (LOX) is a copper-dependent amide oxidase that plays a critical role in the crosslinking of the extracellular matrix (ECM). In this study, we investigated the role of LOX in the pathophysiology of SSc. METHODS/STUDY POPULATION: LOX expression and protein levels were measured in lung tissues and primary fibroblasts from patients with SSc and healthy controls. The effects of recombinant LOX (rLOX) were measured in vitro in primary fibroblasts, ex vivo in human lung tissues and in vivo in mice given bleomycin in combination with rLOX. LOX levels and activity were evaluated in lung fibroblasts treated with an endostatin-derived peptide that ameliorates fibrosis and in mice treated with bleomycin in combination with the peptide. Further, to differentiate the crosslinking activity of LOX from other potential effects, primary human fibroblasts were cultured with rLOX in the presence of the inhibitor, beta-aminopropionitrile. The expression levels of ECM (collagen and fibronectin), pro-fibrotic factors (IL-6 and TGF-beta), and transcription factor (c-Fos) were examined by real-time PCR, ELISA, immunoblotting, or hydroxyproline assay. RESULTS/ANTICIPATED RESULTS: LOX mRNA was increased in lung tissues and matching fibroblasts of SSc patients. rLOX-induced ECM production in vitro and ex vivo in lung fibroblasts and in human lung tissues maintained in organ culture, respectively. Additionally, TGF-beta and bleomycin induced ECM production, LOX mRNA expression and activity. Endostatin peptide abrogated these effects. In vivo, rLOX synergistically exacerbated pulmonary fibrosis in bleomycin-treated mice. The inhibition of LOX catalytic activity by beta-aminopropionitrile failed to abrogate LOX-induced ECM production. LOX increased the production of IL-6. IL-6 neutralization blocked the effects of LOX. Further, LOX induced c-Fos expression and its nuclear localization. DISCUSSION/SIGNIFICANCE OF IMPACT: LOX expression and activity were increased with fibrosis in vitro, ex vivo, and in vivo. LOX induced fibrosis via increasing ECM, IL-6 and c-Fos translocation to the nucleus. These effects were independent of the crosslinking activity of LOX and mediated by IL-6. Our findings suggest that inhibition of LOX may be a viable option for the treatment of lung fibrosis. Further, the use of human lung in organ culture establishes the relevance of our findings to human disease.

scholarly journals Research Models for Studying Vascular Calcification

2020 ◽  
Vol 21 (6) ◽  
pp. 2204 ◽  
Author(s):  
Jaqueline Herrmann ◽  
Milen Babic ◽  
Markus Tölle ◽  
Markus van der Giet ◽  
Mirjam Schuchardt
Keyword(s):  
Animal Models ◽  
Vascular Calcification ◽  
Ex Vivo ◽  
Systemic Disease ◽  
Treatment Options ◽  
Aortic Tissue ◽  
Cardiovascular Morbidity And Mortality ◽  
Culture Models

Calcification of the vessel wall contributes to high cardiovascular morbidity and mortality. Vascular calcification (VC) is a systemic disease with multifaceted contributing and inhibiting factors in an actively regulated process. The exact underlying mechanisms are not fully elucidated and reliable treatment options are lacking. Due to the complex pathophysiology, various research models exist evaluating different aspects of VC. This review aims to give an overview of the cell and animal models used so far to study the molecular processes of VC. Here, in vitro cell culture models of different origins, ex vivo settings using aortic tissue and various in vivo disease-induced animal models are summarized. They reflect different aspects and depict the (patho)physiologic mechanisms within the VC process.

Characterization of a novel peripheral pro-lipolytic mechanism in mice: role of VGF-derived peptide TLQP-21

2011 ◽  
Vol 441 (1) ◽  
pp. 511-522 ◽  
Author(s):  
Roberta Possenti ◽  
Giampiero Muccioli ◽  
Pamela Petrocchi ◽  
Cheryl Cero ◽  
Aderville Cabassi ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Ex Vivo ◽  
Binding Capacity ◽  
Binding Activity ◽  
Metabolic Complications ◽  
Novel Approach ◽  
Receptor Binding Activity ◽  
Treatment Of Obesity

The peptides encoded by the VGF gene are gaining biomedical interest and are increasingly being scrutinized as biomarkers for human disease. An endocrine/neuromodulatory role for VGF peptides has been suggested but never demonstrated. Furthermore, no study has demonstrated so far the existence of a receptor-mediated mechanism for any VGF peptide. In the present study, we provide a comprehensive in vitro, ex vivo and in vivo identification of a novel pro-lipolytic pathway mediated by the TLQP-21 peptide. We show for the first time that VGF-immunoreactivity is present within sympathetic fibres in the WAT (white adipose tissue) but not in the adipocytes. Furthermore, we identified a saturable receptor-binding activity for the TLQP-21 peptide. The maximum binding capacity for TLQP-21 was higher in the WAT as compared with other tissues, and selectively up-regulated in the adipose tissue of obese mice. TLQP-21 increases lipolysis in murine adipocytes via a mechanism encompassing the activation of noradrenaline/β-adrenergic receptors pathways and dose-dependently decreases adipocytes diameters in two models of obesity. In conclusion, we demonstrated a novel and previously uncharacterized peripheral lipolytic pathway encompassing the VGF peptide TLQP-21. Targeting the sympathetic nerve–adipocytes interaction might prove to be a novel approach for the treatment of obesity-associated metabolic complications.

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