scholarly journals Critical Role of Matrix Metalloproteinase 14 in Adipose Tissue Remodeling during Obesity

2020 ◽  
Vol 40 (8) ◽  
Author(s):  
Xin Li ◽  
Yueshui Zhao ◽  
Chuan Chen ◽  
Li Yang ◽  
Hyun-ho Lee ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Transgenic Mice ◽  
Matrix Metalloproteinase ◽  
Early Stage ◽  
Critical Role ◽  
Metabolic Phenotype ◽  
Regulatory Function ◽  
Body Weights ◽  
Adipose Tissue Remodeling

ABSTRACT Fibrosis is recognized as the major pathological change in adipose tissue during the development of obesity. However, the detailed mechanisms governing the interactions between the fibrotic components and their modifiers remain largely unclear. Here, we reported that matrix metalloproteinase 14 (MMP14), a key pericellular collagenase, is dramatically upregulated in obese adipose tissue. We generated a doxycycline-inducible adipose tissue-specific MMP14 overexpression model to study its regulatory function. We found that overexpression of MMP14 in the established obese adipose tissue leads to enlarged adipocytes and increased body weights in transgenic mice. Furthermore, the mice exhibited decreased energy expenditure, impaired lipid metabolism, and insulin resistance. Mechanistically, we found that MMP14 digests collagen 6α3 to produce endotrophin, a potent costimulator of fibrosis and inflammation. Unexpectedly, when overexpressing MMP14 in the early-stage obese adipose tissue, the transgenic mice showed a healthier metabolic profile, including ameliorated fibrosis and inflammation, as well as improved lipid and glucose metabolism. This unique metabolic phenotype is likely due to digestion/modification of the dense adipose tissue extracellular matrix by MMP14, thereby releasing the mechanical stress to allow for its healthy expansion. Understanding these dichotomous impacts of MMP14 provides novel insights into strategies to treat obesity-related metabolic disorders.

Role of proteolysis in development of murine adipose tissue

2008 ◽  
Vol 99 (02) ◽  
pp. 290-294 ◽  
Author(s):  
Valerie Christiaens ◽  
Ilse Scroyen ◽  
H. Roger Lijnen
Keyword(s):  
Cardiovascular Disease ◽  
Extracellular Matrix ◽  
Adipose Tissue ◽  
Transgenic Mice ◽  
Matrix Metalloproteinase ◽  
Proteolytic Activity ◽  
Mortality And Morbidity ◽  
Common Disorder

SummaryObesity is a common disorder, and related diseases such as diabetes, atherosclerosis, hypertension, cardiovascular disease and cancer are a major cause of mortality and morbidity inWesterntype societies. Development of obesity is associated with extensive modifications in adipose tissue involving adipogenesis, angiogenesis and extracellular matrix proteolysis. The fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems cooperate in these processes. A nutritionally induced obesity model in transgenic mice has been used extensively to study the role of the fibrinolytic and MMP systems in the development of obesity. These studies support a role of both systems in adipogenesis and obesity, and suggest that modulation of proteolytic activity may affect development of adipose tissue.

Obesity and vascular risk

2009 ◽  
Vol 29 (01) ◽  
pp. 44-45 ◽  
Author(s):  
H. R. Lijnen
Keyword(s):  
Extracellular Matrix ◽  
Adipose Tissue ◽  
Risk Factor ◽  
Transgenic Mice ◽  
Matrix Metalloproteinase ◽  
Arterial Thrombosis ◽  
Vascular Risk ◽  
Obese Mice ◽  
Thrombotic Complications

SummaryObesity is a common disorder and a known risk factor for vascular thrombotic complications. Development of obesity is associated with extensive modifications in adipose tissue involving adipogenesis, angiogenesis and extracellular matrix proteolysis. Studies using a nutritionally induced obesity model in transgenic mice support a role of the fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems in these processes. Venous or arterial thrombosis models in obese mice confirm a prothrombotic risk associated with obesity.

scholarly journals Evidence for the Regulatory Role of Lipocalin 2 in High-Fat Diet-Induced Adipose Tissue Remodeling in Male Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (10) ◽  
pp. 3525-3538 ◽  
Author(s):  
Hong Guo ◽  
Merlijn Bazuine ◽  
Daozhong Jin ◽  
Merry M. Huang ◽  
Samuel W. Cushman ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Adipocyte Differentiation ◽  
Tissue Remodeling ◽  
Peroxisome Proliferator ◽  
Lipocalin 2 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Adipose Tissue Remodeling ◽  
Fat Depot

Lipocalin 2 (Lcn2) has previously been characterized as an adipokine/cytokine playing a role in glucose and lipid homeostasis. In this study, we investigate the role of Lcn2 in adipose tissue remodeling during high-fat diet (HFD)-induced obesity. We find that Lcn2 protein is highly abundant selectively in inguinal adipose tissue. During 16 weeks of HFD feeding, the inguinal fat depot expanded continuously, whereas the expansion of the epididymal fat depot was reduced in both wild-type (WT) and Lcn2−/− mice. Interestingly, the depot-specific effect of HFD on fat mass was exacerbated and appeared more pronounced and faster in Lcn2−/− mice than in WT mice. In Lcn2−/− mice, adipocyte hypertrophy in both inguinal and epididymal adipose tissue was more profoundly induced by age and HFD when compared with WT mice. The expression of peroxisome proliferator-activated receptor-γ protein was significantly down-regulated, whereas the gene expression of extracellular matrix proteins was up-regulated selectively in epididymal adipocytes of Lcn2−/− mice. Consistent with these observations, collagen deposition was selectively higher in the epididymal, but not in the inguinal adipose depot of Lcn2−/− mice. Administration of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone (Rosi) restored adipogenic gene expression. However, Lcn2 deficiency did not alter the responsiveness of adipose tissue to Rosi effects on the extracellular matrix expression. Rosi treatment led to the further enlargement of adipocytes with improved metabolic activity in Lcn2−/− mice, which may be associated with a more pronounced effect of Rosi treatment in reducing TGF-β in Lcn2−/− adipose tissue. Consistent with these in vivo observations, Lcn2 deficiency reduces the adipocyte differentiation capacity of stromal-vascular cells isolated from HFD-fed mice in these cells. Herein Rosi treatment was again able to stimulate adipocyte differentiation to a similar extent in WT and Lcn2−/− inguinal and epididymal stromal-vascular cells. Thus, combined, our data indicate that Lcn2 has a depot-specific role in HFD-induced adipose tissue remodeling.

scholarly journals Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity

2008 ◽  
Vol 295 (2) ◽  
pp. E313-E322 ◽  
Author(s):  
Can Pang ◽  
Zhanguo Gao ◽  
Jun Yin ◽  
Jin Zhang ◽  
Weiping Jia ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Adipose Tissue ◽  
Tube Formation ◽  
Macrophage Infiltration ◽  
Platelet Derived Growth Factor ◽  
Angiogenic Factor ◽  
Vascular Density ◽  
Adipose Tissue Macrophages ◽  
Adipose Tissue Remodeling

The biological role of macrophage infiltration into adipose tissue in obesity remains to be fully understood. We hypothesize that macrophages may act to stimulate angiogenesis in the adipose tissue. This possibility was examined by determining macrophage expression of angiogenic factor PDGF (platelet-derived growth factor) and regulation of tube formation of endothelial cells by PDGF. The data suggest that endothelial cell density was reduced in the adipose tissue of ob/ob mice. Expression of endothelial marker CD31 was decreased in protein and mRNA. The reduction was associated with an increase in macrophage infiltration. In the obese mice, PDGF concentration was elevated in the plasma, and its mRNA expression was increased in adipose tissue. Macrophages were found to be a major source of PDGF in adipose tissue, as deletion of macrophages led to a significant reduction in PDGF mRNA. In cell culture, PDGF expression was induced by hypoxia, and tube formation of endothelial cells was induced by PDGF. The PDGF activity was dependent on S6K, as inhibition of S6K in endothelial cells led to inhibition of the PDGF activity. We conclude that, in response to the reduced vascular density, macrophages may express PDGF in adipose tissue to facilitate capillary formation in obesity. Although the PDGF level is elevated in adipose tissue, its activity in angiogenesis is dependent on the availability of sufficient endothelial cells. The study suggests a new function of macrophages in the adipose tissue in obesity.

Abstract P050: Novel Mechanism of Ser-496 ERK5 Phosphorylation and Association with p90RSK Is Critical for Regulating C Terminus of Hsc70-Interacting Protein (CHIP) Ubiquitin E3 Ligase Activity in Diabetes-Mediated Exacerbation of Cardiomyocyte Apoptosis and Left Ventricular Dysfunction After Myocardial Infarction

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Nhat-Tu Le ◽  
Yuichiro Takei ◽  
Chang-Hoon Woo ◽  
Tetsuro Shishido ◽  
Yan Lu ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Dysfunction ◽  
Critical Role ◽  
Active Form ◽  
E3 Ligase ◽  
Left Ventricular ◽  
Ang Ii ◽  
Lv Dysfunction ◽  
On Chip

Rationale: Cardiac dysfunction is accelerated in DM patients after MI. Previously, we reported the critical role of ERK5 and CHIP association on CHIP Ub E3 ligase activity, which inhibits inducible cAMP early repressor (ICER)-mediated apoptosis and left ventricle (LV) dysfunction after MI in DM (DM + MI). Yet the regulatory mechanism of ERK5-CHIP has not been established. Objective: Since we found that p90RSK activation was increased in DM heart, we investigated whether p90RSK activation may inhibit ERK5-mediated CHIP activation, and subsequent ICER induction and apoptosis. Methods and Results: The inhibition of p90RSK activation prevented the reduction of ERK5-CHIP binding, CHIP activity, as well as ICER induction and cardiac apoptosis both in vitro after angiotensin II (ang II) stimulation and in vivo after DM + MI. p90RSK and CHIP share a same binding site with ERK5 C-terminal domain (aa571–807), and overexpression of both p90RSK and ERK5 (aa571–807) fragment, but not kinase dead mutant of p90RSK, inhibited ERK5-CHIP association, suggesting the critical role of p90RSK activation on ERK5-CHIP interaction, and competitive nature of p90RSK and CHIP against ERK5 association. Furthermore. LC-MS/MS analysis identified ERK5-S496 as being directly phosphorylated by p90RSK, and ERK5 S496A mutant significantly impaired ang II-mediated inhibition of CHIP Ub ligase activity, suggesting the critical role of Ser-496 phoaphorylation of ERK5 on CHIP activity. Therefore, p90RSK activation is critical for both p90RSK-ERK5 association as well as ERK5-Ser496 phosphorylation, and following disruption of ERK5-CHIP interaction and subsequent inhibition of CHIP Ub ligase activity. The reduction of CHIP Ub ligase activity and LV dysfunction were accelerated both in cardio-specific ERK5 knock out and wild type p90RSK transgenic mice (WT-p90RSK-Tg). Furthermore, double transgenic mice of WT-p90RSK and constitutively active form of MEK5α (specific ERK5 activator) inhibited single WT-p90RSK-Tg-medaited reduction of CHIP Ub ligase activity, LV dysfunction, and improved mortality after MI. Conclusions: These data strongly suggested that p90RSK activation accelerated cardiac dysfunction and apoptosis after DM + MI via inhibiting ERK5-CHIP module.

scholarly journals SIRT3 (Sirtuin-3) Prevents Ang II (Angiotensin II)–Induced Macrophage Metabolic Switch Improving Perivascular Adipose Tissue Function

2020 ◽  
Author(s):  
Tong Wei ◽  
Jing Gao ◽  
Chenglin Huang ◽  
Bei Song ◽  
Mengwei Sun ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Angiotensin Ii ◽  
Metabolic Phenotype ◽  
Inflammasome Activation ◽  
Ang Ii ◽  
Sirtuin 3 ◽  
Metabolic Switch ◽  
Brown Adipocytes ◽  
Perivascular Adipose Tissue

Objective: Infiltrated macrophages actively promote perivascular adipose tissue remodeling and represent a dominant population in the perivascular adipose tissue microenvironment of hypertensive mice. However, the role of macrophages in initiating metabolic inflammation remains uncertain. SIRT3 (sirtuin-3), a NAD-dependent deacetylase, is sensitive to metabolic status and mediates adaptation responses. In this study, we investigated the role of SIRT3-mediated metabolic shift in regulating NLRP3 (Nod-like receptor family pyrin domain-containing 3) inflammasome activation. Approach and Results: Here, we report that Ang II (angiotensin II) accelerates perivascular adipose tissue inflammation and fibrosis, accompanied by NLRP3 inflammasome activation and IL (interleukin)-1β secretion in myeloid SIRT3 knockout (SIRT3 − / − ) mice. This effect is associated with adipose tissue mitochondrial dysfunction. In vitro studies indicate that the deletion of SIRT3 in bone marrow–derived macrophages induces IL-1β production by shifting the metabolic phenotype from oxidative phosphorylation to glycolysis. Mechanistically, SIRT3 deacetylates and activates PDHA1 (pyruvate dehydrogenase E1 alpha) at lysine 83, and the loss of SIRT3 leads to PDH activity decrease and lactate accumulation. Knocking down LDHA (lactate dehydrogenase A) or using carnosine, a buffer against lactic acid, attenuates IL-1β secretion. Furthermore, the blockade of IL-1β from macrophages into brown adipocytes restores thermogenic markers and mitochondrial oxygen consumption. Moreover, NLRP3 knockout (NLRP3 −/− ) mice exhibited reduced IL-1β production while rescuing the mitochondrial function of brown adipocytes and alleviating perivascular adipose tissue fibrosis. Conclusions: SIRT3 represents a potential therapeutic target to attenuate NLRP3-related inflammation. Pharmacological targeting of glycolytic metabolism may represent an effective therapeutic approach.

scholarly journals Excessive Neutrophil Extracellular Trap Formation Aggravates Acute Myocardial Infarction Injury in Apolipoprotein E Deficiency Mice via the ROS-Dependent Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Zheliang Zhou ◽  
Shuning Zhang ◽  
Suling Ding ◽  
Mieradilijiang Abudupataer ◽  
Zhiwei Zhang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Apolipoprotein E ◽  
Myocardial Injury ◽  
Early Stage ◽  
Critical Role ◽  
Neutrophil Extracellular Trap ◽  
Coronary Artery Ligation ◽  
Infarct Zone ◽  
Dependent Pathway

Genetically human apolipoprotein E (APOE) ε32 is associated with a decreased risk of ischemic heart disease. ApoE deficiency in mice impairs infarct healing after myocardial infarction (MI). After the ischemic injury, a large number of neutrophils are firstly recruited into the infarct zone and then degrade dead material and promote reparative phase transformation. The role of ApoE in inflammation response in the early stage of MI remains largely unclear. In this study, we investigated the effect of ApoE deficiency on neutrophils’ function and myocardial injury after myocardial infarction. By left coronary artery ligation in ApoE-/- and wild-type (WT) mice, we observed increased infarct size and neutrophil infiltration in ApoE-/- mice. Within the infarct zone, more neutrophil extracellular traps (NETs) were observed in ApoE-/- mice, while increased ex vivo NET formation was detected in ApoE-/- mouse-derived neutrophils through the NADPH oxidase-ROS-dependent pathway. Suppressing overproduced NETs reduced myocardial injury in ApoE-/- mice after ligation. In general, our findings reveal a critical role of apolipoprotein E in regulating Ly6G+ neutrophil activation and NET formation, resulting in limiting myocardial injury after myocardial infarction. In such a process, apolipoprotein E regulates NET formation via the ROS-MAPK-MSK1 pathway.

scholarly journals Metabolic reprogramming via PPARα signaling in cardiac hypertrophy and failure: From metabolomics to epigenetics

2017 ◽  
Vol 313 (3) ◽  
pp. H584-H596 ◽  
Author(s):  
Junco Shibayama Warren ◽  
Shin-ichi Oka ◽  
Daniela Zablocki ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Current Knowledge ◽  
Critical Role ◽  
Cardiac Metabolism ◽  
Metabolic Reprogramming ◽  
Metabolic Phenotype ◽  
Global Changes ◽  
Peroxisome Proliferator ◽  
Metabolic Remodeling

Studies using omics-based approaches have advanced our knowledge of metabolic remodeling in cardiac hypertrophy and failure. Metabolomic analysis of the failing heart has revealed global changes in mitochondrial substrate metabolism. Peroxisome proliferator-activated receptor-α (PPARα) plays a critical role in synergistic regulation of cardiac metabolism through transcriptional control. Metabolic reprogramming via PPARα signaling in heart failure ultimately propagates into myocardial energetics. However, emerging evidence suggests that the expression level of PPARα per se does not always explain the energetic state in the heart. The transcriptional activities of PPARα are dynamic, yet highly coordinated. An additional level of complexity in the PPARα regulatory mechanism arises from its ability to interact with various partners, which ultimately determines the metabolic phenotype of the diseased heart. This review summarizes our current knowledge of the PPARα regulatory mechanisms in cardiac metabolism and the possible role of PPARα in epigenetic modifications in the diseased heart. In addition, we discuss how metabolomics can contribute to a better understanding of the role of PPARα in the progression of cardiac hypertrophy and failure.

scholarly journals Limited Role of Mincle in the Host Defense against Infection with Cryptococcus deneoformans

2020 ◽  
Vol 88 (11) ◽  
Author(s):  
Yuki Sato ◽  
Ko Sato ◽  
Hideki Yamamoto ◽  
Jun Kasamatsu ◽  
Tomomitsu Miyasaka ◽  
...  
Keyword(s):  
Host Defense ◽  
Early Stage ◽  
Critical Role ◽  
Yeast Cells ◽  
Dependent Manner ◽  
Th2 Response ◽  
Lectin Receptors ◽  
Cryptococcal Infection ◽  
Tnf Α

ABSTRACT Cryptococcus deneoformans is an opportunistic fungal pathogen that frequently causes fatal meningoencephalitis in patients with impaired cell-mediated immune responses such as AIDS. Caspase-associated recruitment domain 9 (CARD9) plays a critical role in the host defense against cryptococcal infection, suggesting the involvement of one or more C-type lectin receptors (CLRs). In the present study, we analyzed the role of macrophage-inducible C-type lectin (Mincle), one of the CLRs, in the host defense against C. deneoformans infection. Mincle expression in the lungs of wild-type (WT) mice was increased in the early stage of cryptococcal infection in a CARD9-dependent manner. In Mincle gene-disrupted (Mincle KO) mice, the clearance of this fungus, pathological findings, Th1/Th2 response, and antimicrobial peptide production in the infected lungs were nearly comparable to those in WT mice. However, the production of interleukin-22 (IL-22), tumor necrosis factor alpha (TNF-α), and IL-6 and the expression of AhR were significantly decreased in the lungs of Mincle KO mice compared to those of WT mice. In in vitro experiments, TNF-α production by bone marrow-derived dendritic cells was significantly decreased in Mincle KO mice. In addition, the disrupted lysates of C. deneoformans, but not those of whole yeast cells, activated Mincle-triggered signaling in an assay with a nuclear factor of activated T cells (NFAT)-green fluorescent protein (GFP) reporter cells expressing this receptor. These results suggest that Mincle may be involved in the production of Th22-related cytokines at the early stage of cryptococcal infection, although its role may be limited in the host defense against infection with C. deneoformans.

scholarly journals Modeling Adipogenesis: Current and Future Perspective

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2326 ◽  
Author(s):  
Hisham F. Bahmad ◽  
Reem Daouk ◽  
Joseph Azar ◽  
Jiranuwat Sapudom ◽  
Jeremy C. M. Teo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adipose Tissue ◽  
Crucial Role ◽  
Critical Role ◽  
Treatment Modalities ◽  
Future Perspective ◽  
Adipose Derived Stem Cells ◽  
Physiological Importance ◽  
And Personalized Medicine

Adipose tissue is contemplated as a dynamic organ that plays key roles in the human body. Adipogenesis is the process by which adipocytes develop from adipose-derived stem cells to form the adipose tissue. Adipose-derived stem cells’ differentiation serves well beyond the simple goal of producing new adipocytes. Indeed, with the current immense biotechnological advances, the most critical role of adipose-derived stem cells remains their tremendous potential in the field of regenerative medicine. This review focuses on examining the physiological importance of adipogenesis, the current approaches that are employed to model this tightly controlled phenomenon, and the crucial role of adipogenesis in elucidating the pathophysiology and potential treatment modalities of human diseases. The future of adipogenesis is centered around its crucial role in regenerative and personalized medicine.

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