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Project description:Myostatin (MSTN) has been discovered as a critical regulator of muscle mass. Recently, there has been an increasing interest in its functions in metabolism. Here, we specific knocked out MSTN in brown adipose tissue (BAT) (MSTNΔUCP1), and found that the MSTNΔUCP1 mice gained more weight than controls on high-fat diet, with progressive hepatosteatosis, and impaired skeletal muscle activity. RNA-seq analysis indicated signatures of mitochondrial dysfunction and inflammation in MSTN-ablation BAT. Further studies demonstrated that KLF4 is required for the metabolic phenotypes and FGF21 contributes to the microenvironment communication between adipocytes and macrophages induced by loss of MSTN in BAT. Moreover, MSTN-SMAD2/3-p38 signaling pathway mediated the expression of KLF4 and FGF21 in adipocytes. Taken together, brown adipocytes-derived MSTN governs metabolic niche in BAT and regulates systemic energy homeostasis.
2024-07-23 | GSE249029 | GEO
Project description:Myostatin (MSTN) has been discovered as a critical regulator of muscle mass. Recently, there has been an increasing interest in its functions in metabolism. Here, we specific knocked out MSTN in brown adipose tissue (BAT) (MSTNΔUCP1), and found that the MSTNΔUCP1 mice gained more weight than controls on high-fat diet, with progressive hepatosteatosis, and impaired skeletal muscle activity. RNA-seq analysis indicated signatures of mitochondrial dysfunction and inflammation in MSTN-ablation BAT. Further studies demonstrated that KLF4 is required for the metabolic phenotypes and FGF21 contributes to the microenvironment communication between adipocytes and macrophages induced by loss of MSTN in BAT. Moreover, MSTN-SMAD2/3-p38 signaling pathway mediated the expression of KLF4 and FGF21 in adipocytes. Taken together, brown adipocytes-derived MSTN governs metabolic niche in BAT and regulates systemic energy homeostasis.
2024-07-23 | GSE249028 | GEO
Project description:Myostatin (MSTN) has long been recognized as a critical regulator of muscle mass. Recently, there has been increasing interest in its role in metabolism. In our study, we specifically knocked out MSTN in brown adipose tissue (BAT) from mice (MSTNΔUCP1) and found that the mice gained more weight than did controls when fed a high-fat diet, with progressive hepatosteatosis and impaired skeletal muscle activity. RNA-Seq analysis indicated signatures of mitochondrial dysfunction and inflammation in the MSTN-ablated BAT. Further studies demonstrated that Kruppel-like factor 4 (KLF4) was responsible for the metabolic phenotypes observed, whereas fibroblast growth factor 21 (FGF21) contributed to the microenvironment communication between adipocytes and macrophages induced by the loss of MSTN. Moreover, the MSTN/SMAD2/3-p38 signaling pathway mediated the expression of KLF4 and FGF21 in adipocytes. In summary, our findings suggest that brown adipocyte-derived MSTN regulated BAT thermogenesis via autocrine and paracrine effects on adipocytes or macrophages, ultimately regulating systemic energy homeostasis.
| S-EPMC11324308 | biostudies-literature
Project description:Brown adipose tissue (BAT) is a promising potential therapeutic target for the treatment of obesity and related metabolic diseases. Allicin, a natural product in garlic, has multiple biological and pharmacological functions. However, the role of allicin in the regulation of metabolic organs, particularly BAT activation, has not been well studied. Here, we show that allicin imparts a significant effect by inhibiting body weight gain, decreasing adiposity, maintaining glucose homeostasis, improving insulin resistance, and ameliorating hepatic steatosis in obese mice. These observations strongly correlate with the activation of BAT. Notably, allicin plays a role in BAT activation, which may partly contribute to the Sirt1-PGC1?-Tfam pathway. In addition, allicin can significantly increase the succinylation levels of UCP1 in BAT by inhibiting sirt5, whereas excess allicin induces autophagy/mitophagy and mitochondrial dysfunction. Thus, our findings point to allicin as a promising therapeutic approach for the treatment of obesity and metabolic disorders.
| S-EPMC7226876 | biostudies-literature
Project description:The tumor microenvironment is abundant with exosomes that are secreted by the cancer cells themselves. Exosomes are nanosized, organelle-like membranous structures that are increasingly being recognized as major contributors in the progression of malignant neoplasms. A critical element in melanoma progression is its propensity to metastasize, but little is known about how melanoma cell-derived exosomes modulate the microenvironment to optimize conditions for tumor progression and metastasis. Here, we provide evidence that melanoma cell-derived exosomes promote phenotype switching in primary melanocytes through paracrine/autocrine signaling. We found that the mitogen-activated protein kinase (MAPK) signaling pathway was activated during the exosome-mediated epithelial-to-mesenchymal transition (EMT)-resembling process, which promotes metastasis. Let-7i, an miRNA modulator of EMT, was also involved in this process. We further defined two other miRNA modulators of EMT (miR-191 and let-7a) in serum exosomes for differentiating stage I melanoma patients from non-melanoma subjects. These results provide the first strong molecular evidence that melanoma cell-derived exosomes promote the EMT-resembling process in the tumor microenvironment. Thus, novel strategies targeting EMT and modulating the tumor microenvironment may emerge as important approaches for the treatment of metastatic melanoma.
| S-EPMC4869527 | biostudies-literature
Project description:Mesenchymal stem cells (MSCs) transplanted into injured myocardium promote repair through paracrine mechanisms. We have previously shown that MSCs over-expressing AKT1 (Akt-MSCs) exhibit enhanced properties for cardiac repair. In this study, we investigated the relevance of Abi3bp toward MSC biology. Abi3bp formed extracellular deposits with expression controlled by Akt1 and ubiquitin-mediated degradation. Abi3bp knockdown/knockout stabilized focal adhesions and promoted stress-fiber formation. Furthermore, MSCs from Abi3bp knockout mice displayed severe deficiencies in osteogenic and adipogenic differentiation. Knockout or stable knockdown of Abi3bp increased MSC and Akt-MSC proliferation, promoting S-phase entry via cyclin-d1, ERK1/2, and Src. Upon Abi3bp binding to integrin-?1 Src associated with paxillin which inhibited proliferation. In vivo, Abi3bp knockout increased MSC number and proliferation in bone marrow, lung, and liver. In summary, we have identified a novel extracellular matrix protein necessary for the switch from proliferation to differentiation in MSCs.
| S-EPMC3775980 | biostudies-literature
Project description:Recent studies suggest that SOCS2 is involved in the regulation of TLR signaling. In this study, we found that the expression of SOCS2 is regulated in human monocyte-derived DC by ligands stimulating TLR2, 3, 4, 5, 8 and 9 signaling. SOCS2 induction by LPS was dependent on the type I IFN regulated transcription factors IRF1 and IRF3 as shown by using silencing RNAs for IRFs. Blocking endogenous type I IFN signaling, by neutralizing antibodies to the receptor IFNAR2, abolished SOCS2 mRNA expression after TLR4 stimulation. Transcription factors STAT3, 5 and 6 displayed putative binding sites in the promoter regions of the human SOCS2 gene. Subsequent silencing experiments further supported that STAT3 and STAT5 are involved in LPS induced SOCS2 regulation. In mice we show that SOCS2 mRNA induction is 45% lower in bone marrow derived macrophages derived from MyD88(-/-) mice, and do not increase in BMMs from IRF3(-/-) mice after BCG infection. In conclusion, our results suggest that TLR4 signaling indirectly increases SOCS2 in late phase mainly via the production of endogenous type I IFN, and that subsequent IFN receptor signaling activates SOCS2 via STAT3 and STAT5.
| S-EPMC3264591 | biostudies-literature
Project description:Giant Cell Tumor of Bone (GCT) is an aggressive skeletal tumor characterized by local bone destruction, high recurrence rates and metastatic potential. Previous work in our lab has shown that the neoplastic cell of GCT is a proliferating pre-osteoblastic stromal cell in which the transcription factor Runx2 plays a role in regulating protein expression. One of the proteins expressed by these cells is parathyroid hormone-related protein (PTHrP). The objectives of this study were to determine the role played by PTHrP in GCT of bone with a focus on cell proliferation and apoptosis. Primary stromal cell cultures from 5 patients with GCT of bone and one lung metastasis were used for cell-based experiments. Control cell lines included a renal cell carcinoma (RCC) cell line and a human fetal osteoblast cell line. Cells were exposed to optimized concentrations of a PTHrP neutralizing antibody and were analyzed with the use of cell proliferation and apoptosis assays including mitochondrial dehydrogenase assays, crystal violet assays, APO-1 ELISAs, caspase activity assays, flow cytometry and immunofluorescent immunohistochemistry. Neutralization of PTHrP in the cell environment inhibited cell proliferation in a consistent manner and induced apoptosis in the GCT stromal cells, with the exception of those obtained from a lung metastasis. Cell cycle progression was not significantly affected by PTHrP neutralization. These findings indicate that PTHrP plays an autocrine/paracrine neoplastic role in GCT by allowing the proliferating stromal cells to evade apoptosis, possibly through non-traditional caspase-independent pathways. Thus PTHrP neutralizing immunotherapy is an intriguing potential therapeutic strategy for this tumor.
| S-EPMC3100318 | biostudies-literature
Project description:Genomic imprinting is implicated in the control of gene dosage in neurogenic niches. Here we address the importance of Igf2 imprinting for murine adult neurogenesis in the subventricular zone (SVZ) and in the subgranular zone (SGZ) of the hippocampus in vivo. In the SVZ, paracrine IGF2 is a cerebrospinal fluid and endothelial-derived neurogenic factor requiring biallelic expression, with mutants having reduced activation of the stem cell pool and impaired olfactory bulb neurogenesis. In contrast, Igf2 is imprinted in the hippocampus acting as an autocrine factor expressed in neural stem cells (NSCs) solely from the paternal allele. Conditional mutagenesis of Igf2 in blood vessels confirms that endothelial-derived IGF2 contributes to NSC maintenance in SVZ but not in the SGZ, and that this is regulated by the biallelic expression of IGF2 in the vascular compartment. Our findings indicate that a regulatory decision to imprint or not is a functionally important mechanism of transcriptional dosage control in adult neurogenesis.
| S-EPMC4579569 | biostudies-literature
Project description:Sphingosine-1-phosphate-induced ?1B-adrenergic receptor desensitization and phosphorylation were studied in rat-1 fibroblasts stably expressing enhanced green fluorescent protein-tagged adrenoceptors. Sphingosine-1-phosphate induced adrenoceptor desensitization and phosphorylation through a signaling cascade that involved phosphoinositide 3-kinase and protein kinase C activities. The autocrine/paracrine role of sphingosine-1-phosphate was also studied. It was observed that activation of receptor tyrosine kinases, such as insulin growth factor-1 (IGF-I) and epidermal growth factor (EGF) receptors increased sphingosine kinase activity. Such activation and consequent production of sphingosine-1-phosphate appear to be functionally relevant in IGF-I- and EGF-induced ?1B-adrenoceptor phosphorylation and desensitization as evidenced by the following facts: a) expression of a catalytically inactive (dominant-negative) mutant of sphingosine kinase 1 or b) S1P1 receptor knockdown markedly reduced this growth factor action. This action of sphingosine-1-phosphate involves EGF receptor transactivation. In addition, taking advantage of the presence of the eGFP tag in the receptor construction, we showed that S1P was capable of inducing ?1B-adrenergic receptor internalization and that its autocrine/paracrine generation was relevant for internalization induced by IGF-I. Four distinct hormone receptors and two autocrine/paracrine mediators participate in IGF-I receptor-?1B-adrenergic receptor crosstalk.
| S-EPMC3273635 | biostudies-literature