Gpnmb secreted from liver promotes lipogenesis in white adipose tissue and aggravates obesity and insulin resistance
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ABSTRACT:
PROVIDER: PRJNA530742 | ENA |
REPOSITORIES: ENA
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Project description:Metabolism in mammals is regulated by the complex interplay among different organs. Fatty acid synthesis is increased in white adipose tissue (WAT) when it is inhibited in liver. Here we identify glycoprotein nonmetastatic melanoma protein B (Gpnmb) as one liver-WAT cross-talk factor in lipogenesis. Hepatic SREBP pathway inhibition leads to increased transcription of the Gpnmb and promotes the processing of the membrane protein to a secreted form. Gpnmb stimulates lipogenesis in WAT and exacerbates diet-induced obesity and insulin resistance. In humans, Gpnmb is tightly associated with body mass index and is a strong risk factor for obesity. Gpnmb inhibition by a neutralizing antibody or liver specific knockdown improves metabolic parameters including weight gain reduction and increased insulin sensitivity, likely by promoting the beiging of WAT. These results suggest that Gpnmb is a liver-secreted factor regulating lipogenesis in WAT, and that Gpnmb inhibition may provide a therapeutic strategy for obesity and diabetes. Hepatic SREBP pathway inhibition, such as liver-specific ablation of Scap (L-Scap-/-), decreases fatty acid synthesis in liver. Meanwhile, the fatty acid synthesis in white adipose tissue of L-Scap-/- is compensatorily increased. The microarray analysis using the liver RNAs of L-Scap-/- and wild type (WT) mice is performed to identify the up-regulated genes encoding secreted factors in L-Scap-/-.
2019-04-04 | GSE129283 | GEO
Project description:The expression of the soluble protein GPNMB (glycoprotein non-metastatic melanoma protein B) induces an aggressive behavior of tumor cells by promoting proliferation and distant spread. The main molecular feature is the over expression of interleukin Il-33. The gene profile of MCA-1-GPNMB and MCA-1-GPNMB-spheroid cell line was assessed against MCA-1-Mock.
2020-07-30 | E-MTAB-8082 | biostudies-arrayexpress
Project description:Insulin integrates hepatic glucose and lipid metabolism, directing nutrients to storage as glycogen and triglyceride. In type 2 diabetes, levels of the former are low and the latter are exaggerated, posing a pathophysiologic and therapeutic conundrum. A branching model1 of insulin signaling, with FoxO1 presiding over glucose production2-5 and Srebp–1c regulating lipogenesis,6-8 provides a potential explanation. Here we illustrate an alternative mechanism that integrates glucose production and lipogenesis under the unifying control of FoxO. Liver–specific ablation of three FoxOs (L–FoxO1,3,4) prevents the induction of glucose–6–phosphatase and the repression of glucokinase during fasting, thus increasing lipogenesis at the expense of glucose production. We document a similar pattern in the early phases of diet-induced insulin resistance, and propose that FoxOs are required to enable the liver to direct nutritionally derived carbons to glucose vs. lipid metabolism. Our data underscore the heterogeneity of hepatic insulin resistance during progression from the metabolic syndrome to overt diabetes, and the conceptual challenge of designing therapies that curtail glucose production without promoting hepatic lipid accumulation. We used microarrays to detail the change of gene expression in liver after knocking out FoxO1,3 and 4. Liver tissue samples were collected from hepatocyte- specific triple FoxO(1,3, and 4) KO and their littermates control (WT) mice after fasting (22 h) or refeeding (4 h). Gene expression was analyzed by microarray. Mice were on a mixed background of C57BL/6J and 129.
2014-08-20 | E-GEOD-60527 | biostudies-arrayexpress
Project description:Adipocytes are a major source of secreted small extracellular vesicles (sEVs), which carry various cargo including small non-coding RNAs (smRNAs) and miRNAs to distal cells. Several miRNAs have been implicated in obesity and insulin resistance, and since they function like adipokines, we sought to assess whether insulin can regulate their secretion into sEVs from adipocytes.
2024-09-13 | GSE269536 | GEO
Project description:Gaucher disease (GD) is characterized by the presence of glucosylceramide-laden macrophages (Gaucher cells) as the result of deficiency in the lysosomal hydrolase glucocerebrosidase (GBA). Non-neuronopathic type 1 GD is effectively treated by infusions with macrophage-targeted recombinant glucocerebrosidase. We here report how LC-MSE analysis of the proteome of laser-dissected splenic Gaucher cells revealed high expression of several proteins amongst which was gpNMB. This was confirmed by histochemistry and RNA quantification. Macrophages produce gpNMB as membrane protein but release soluble fragments. In plasma of symptomatic Gaucher patients (n=59) soluble gpNMB was next found to be on average 25-fold increased prior to treatment, without overlap with control values, (control mean: 20 ng/ml; range 11-34 ng/ml vs. GD mean: 495 ng/ml; range: 137-1283 ng/ml).
2016-09-27 | PXD001598 | Pride
Project description:Insulin integrates hepatic glucose and lipid metabolism, directing nutrients to storage as glycogen and triglyceride. In type 2 diabetes, levels of the former are low and the latter are exaggerated, posing a pathophysiologic and therapeutic conundrum. A branching model1 of insulin signaling, with FoxO1 presiding over glucose production2-5 and Srebp–1c regulating lipogenesis,6-8 provides a potential explanation. Here we illustrate an alternative mechanism that integrates glucose production and lipogenesis under the unifying control of FoxO. Liver–specific ablation of three FoxOs (L–FoxO1,3,4) prevents the induction of glucose–6–phosphatase and the repression of glucokinase during fasting, thus increasing lipogenesis at the expense of glucose production. We document a similar pattern in the early phases of diet-induced insulin resistance, and propose that FoxOs are required to enable the liver to direct nutritionally derived carbons to glucose vs. lipid metabolism. Our data underscore the heterogeneity of hepatic insulin resistance during progression from the metabolic syndrome to overt diabetes, and the conceptual challenge of designing therapies that curtail glucose production without promoting hepatic lipid accumulation. We used microarrays to detail the change of gene expression in liver after knocking out FoxO1,3 and 4.
2014-08-20 | GSE60527 | GEO
Project description:Many risk loci for Parkinson’s disease (PD) have been identified by genome-wide association studies (GWAS), but target genes and mechanisms remain largely unknown. We linked the GWAS-derived chromosome 7 locus (sentinel SNP rs199347) to GPNMB, through colocalization analyses of expression quantitative trait locus (eQTL) and PD risk signals, confirmed by allele-specific expression studies in human brain. In cells, Glycoprotein Nonmetastatic Melanoma Protein B protein (GPNMB) co-immunoprecipitated and co-localized with alpha-synuclein (aSyn). In induced pluripotent stem cell-derived neurons, loss of GPNMB resulted in loss of ability to internalize aSyn fibrils and develop aSyn pathology. In 781 PD and 59 control biosamples, GPNMB was elevated in PD plasma, associating with disease severity. Thus, GPNMB represents a PD risk gene, with potential for biomarker development and therapeutic targeting.
2022-06-17 | GSE206327 | GEO
Project description:The aim of this study was to detect and functionally investigate miRNAs linked to insulin sensitivity in human subcutaneous white adipose tissue (scWAT). Subjects were selected based on the insulin-stimulated lipogenesis response of subcutaneous adipocytes. Eleven miRNAs displayed differential expression between OIR and OIS states. Overexpression of miR-143-3p and miR-652-3p increased insulin-stimulated lipogenesis in human in vitro-differentiated adipocytes. MicroRNAs-143-3p and -652-3p are linked to scWAT insulin resistance independently of obesity.
2017-05-01 | GSE87379 | GEO
Project description:RNA-seq analysis of livers from control mice, mice with adult onset, hepatocyte-specific GH receptor (GHR) deficiency, and GHR-deficient mice combined with IGF1 expression or expression of constitutively active ('CA') STAT5b. This dataset is part of a large study showing that adult-onset loss of hepatocyte GHR signaling increases steatosis, associated with enhanced glucokinase activity, de novo lipogenesis (DNL) and pathway selective hepatic insulin resistance.
2023-08-21 | GSE222513 | GEO
Project description:Levels of Glyco Protein Non-metastatic Melanoma protein B (GPNMB), a type I transmembrane protein, originally identified in non-metastatic melanomas has been shown to be strongly associated with human heart failure. However, the role of GPNMB in modulation of cardiac injury and cardiac function remains unclear. We analyzed human cardiac global gene expression data sets and observed increased GPNMB expression in failing hearts. In murine hearts after myocardial infarction (MI), we showed that GPNMB expression increased by an order of magnitude. Lineage tracing and bone marrow transplantation experiments demonstrated that bone marrow macrophages were the primary source of GPNMB in the injured heart. Using genetic loss of function approaches, we demonstrate that animals deficient in GPNMB exhibited significantly higher mortality, cardiac rupture and developed rapid post infarct LV dysfunction. Conversely gain of function approaches by increasing circulating GPNMB levels by viral delivery led to augmentation of post MI heart function. Single cell transcriptomics demonstrated pleiotropic effects of GPNMB on gene expression of myocytes and non-myocytes leading to enhanced myocyte contraction and decreased fibroblast activation. Using chemical cross-linking studies and immunoprecipitation studies, we identified the orphan receptor GPR39 as a receptor for circulating GPNMB. In animals deficient in GPR39, GPNMB failed to deliver beneficial effects on post infarct heart function. Taken together, these observations demonstrate that bone marrow macrophage derived GPNMB plays a pivotal role in cardiac repair following myocardial infarction, by mediating its pleiotropic effects in part via the orphan receptor GPR39
2024-09-17 | GSE277086 | GEO