Obesity-linked suppression of MBOAT7 promotes liver injury
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PROVIDER: PRJNA577868 | ENA |
REPOSITORIES: ENA
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Project description:This SuperSeries is composed of the SubSeries listed below.
2019-10-17 | GSE138947 | GEO
Project description:An understanding of the mechanisms regulating white adipose tissue (WAT) formation is key for developing of new tools to treat obesity and its related diseases. Here, we identify DEPTOR as a positive regulator of adipogenesis whose expression is associated with obesity. In a polygenic mouse model of obesity/leanness, Deptor is part of the Fob3a QTL linked to obesity and we fine that Deptor is the highest priority candidate gene regulating WAT accumulation in this model. Using a doxycycline-inducible mouse model for Deptor overexpression, we confirmed that Deptor promotes WAT expansion in vivo. DEPTOR expression is elevated in WAT of obese humans and strongly correlates with the degree of obesity. We show that DEPTOR is induced during adipogenesis and that its overexpression cell-autonomously promotes, while its suppression blocks, adipogenesis. DEPTOR positively regulates adipogenesis by promoting the activity of the pro-adipogenic factors Akt/PKB and PPAR-gamma. These results establish DEPTOR as a physiological regulator of adipogenesis and provide new insights into the molecular mechanisms controlling WAT formation. 2 groups of F2 mice for opossing genotype at Fob3a QTL (FF versus VV) - parental strains of the F2 cross were the Fat line and congenic V-line; 5 biological replications per group; reference for Fat line: Horvat S. et al. (2000) MAMMALIAN GENOME 11(1): 2-7
2012-08-14 | E-GEOD-38321 | biostudies-arrayexpress
Project description:This result is expected to identify several lncRNAs and mRNAs that are dysregulated in the lung due to obesity, as well as obesity-associated lncRNAs and mRNAs that are further altered in acute lung injury, as biomarkers specific to obesity-associated acute lung injury. To provide useful information for elucidating the development of acute lung injury exacerbated by obesity and exploring potential therapeutic targets
2024-01-30 | GSE229262 | GEO
Project description:An understanding of the mechanisms regulating white adipose tissue (WAT) formation is key for developing of new tools to treat obesity and its related diseases. Here, we identify DEPTOR as a positive regulator of adipogenesis whose expression is associated with obesity. In a polygenic mouse model of obesity/leanness, Deptor is part of the Fob3a QTL linked to obesity and we fine that Deptor is the highest priority candidate gene regulating WAT accumulation in this model. Using a doxycycline-inducible mouse model for Deptor overexpression, we confirmed that Deptor promotes WAT expansion in vivo. DEPTOR expression is elevated in WAT of obese humans and strongly correlates with the degree of obesity. We show that DEPTOR is induced during adipogenesis and that its overexpression cell-autonomously promotes, while its suppression blocks, adipogenesis. DEPTOR positively regulates adipogenesis by promoting the activity of the pro-adipogenic factors Akt/PKB and PPAR-gamma. These results establish DEPTOR as a physiological regulator of adipogenesis and provide new insights into the molecular mechanisms controlling WAT formation.
2012-08-15 | GSE38321 | GEO
Project description:Thrombospondin 1 (TSP1) is a multifunctional matricellular protein. Previously we have shown that TSP1 plays an important role in obesity-associated metabolic complications including inflammation, insulin resistance, cardiovascular and renal disease. However, its contribution to obesity-associated non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) remains largely unknown and is determined in this study. High fat diet or AMLN diet-induced obese and insulin resistant NAFLD/NASH mouse models were utilized. In addition, tissue specific TSP1 knockout mice were utilized to determine the contribution of different cellular sources of obesity-induced TSP1 to NAFLD/NASH development. The data demonstrated that liver TSP1 levels were increased in experimental obese and insulin resistant NAFLD/NASH mouse models as well as in human obese NASH patients. Moreover, TSP1 deletion in hepatocyte or adipocytes did not protect mice from diet-induced NAFLD/NASH. However, myeloid/macrophage-specific TSP1 deletion protected mice against obesity-associated liver injury, accompanied by reduced liver inflammation and fibrosis. Importantly, this protection is independent of the levels of obesity and hepatic steatosis. Mechanistically, through an autocrine effect, macrophage-derived TSP1 suppressed SMPDL3B expression in liver, which amplified liver pro-inflammatory signaling (TLR4 signal pathway) and promoted NAFLD progression. Together, out data suggest that macrophage-derived TSP1 is a significant contributor to obesity-associated NAFLD/NASH development and progression and may serve as a therapeutic target for this disease.
2020-12-07 | GSE155973 | GEO
Project description:Impact of Diet Induced Obesity on Hyperoxic Lung Injury
| PRJNA510361 | ENA
Project description:Visceral adipose tissue fibrosis is linked to metabolic dysfunction in obesity; however, critical cell types that trigger and contribute to fibrosis in this depot are not completely understood. Whether adipose mesothelial cells (AMCs) play a role in pathologic obesity has been unclear.
2022-12-01 | GSE128665 | GEO
Project description:Obesity exacerbates inflammation upon lung injury; however, the mechanisms by which obesity primes pulmonary dysregulation prior to injury are not well studied. Notably, little is known about how obesity dysregulates pulmonary polyunsaturated fatty acid (PUFA) metabolism that is central to inflammation initiation and resolution. Herein, we first show that a high fat diet (HFD) administered to C57BL/6J mice increases the relative abundance of pulmonary PUFA-containing triglycerides and the concentration of PUFA-derived oxylipins, independent of an increase in total pulmonary PUFAs, prior to onset of pulmonary inflammation. Experiments with a genetic model of obesity did not recapitulate the effects of the HFD on the pulmonary oxylipin signature, revealing a diet-driven effect. Subsequent pulmonary next-generation RNA sequencing identified complex and unique transcriptional regulation with the HFD. The HFD increased pathways related to glycerophospholipid metabolism and immunity, including an elevation in B cell differentiation and signaling. Finally, computational integration of lipidomic with transcriptomic data revealed novel HFD-driven networks between glycerophospholipid metabolism and B cell receptor signaling with specific PUFA-derived oxylipins. Collectively, these data show obesity dysregulates pulmonary PUFA metabolism prior to lung injury, which may be a mechanism by which obesity primes the lungs to respond poorly upon infectious and/or inflammatory challenges.
2022-09-28 | GSE194403 | GEO
Project description:Background: Obesity has become a worldwide concern. Acute respiratory distress syndrome (ARDS) comprises 10.4% of total intensive care unit admissions and is associated with very high mortality. ARDS incidence is increased in obese patients. Exposure of rodents to hyperoxia mimics many of the clinical and pathologic features observed in patients with ARDS. The aim of this study was to determine the impact of high fat diet-induced obesity on the susceptibility to hyperoxic acute lung injury in mice. Methods: Male C57BL/6 mice received 60% fat versus ingredient matched 10% fat diet. Mice were exposed to >95% oxygen to induce lung damage. RNA was isolated from lung homogenates and by comparing RNA sequencing results with mouse Mitocarta, an inventory of genes encoding proteins with mitochondrial localization, we identified fatty acid synthase (FASN), an enzyme catalyzing de novo fatty acid synthesis, as one of the mitochondrial genes significantly changed with diet and with hyperoxia. We generated mice deficient in FASN in alveolar epithelial cells by using a tamoxifen inducible Cre recombinase construct (FASNflox/flox SPC Cre+/-) and subjected them to hyperoxia and high fat diet. Results: Mice receiving 60% fat diet had significantly higher weight, serum cholesterol and fasting glucose. High fat diet mice had significantly reduced survival and increased lung damage, as assessed by BAL protein and LDH, histology and TUNEL staining. By RNA sequencing of lung homogenates we identified FASN as one of the mitochondrial genes significantly reduced in mice receiving 60% compared to 10% fat diet and further reduced with hyperoxia. We confirmed that FASN protein levels in the lung of high fat diet mice were lower by immunoblotting and immunohistochemistry. After 48 hours of hyperoxia FASNflox/flox SPC Cre+/- mice displayed increased levels of BAL protein and LDH and more severe histologic lung injury. FASNflox/flox SPC Cre+/- mice remained more prone to lung injury after hyperoxic exposure even when they received 60% fat diet. Conclusions: These results demonstrate that obesity increases the severity of hyperoxia induced acute lung injury in mice by altering FASN levels in the lung of high fat diet fed rodents. To our knowledge, this is the first study to show that high fat diet leads to altered FASN expression in the lung and that both high fat diet and reduced FASN in alveolar epithelial cells lead to increased lung injury under hyperoxic conditions.
2019-07-25 | GSE123938 | GEO
Project description:Aims: Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we investigate the role of Heart and neural crest derivatives-expressed protein 2 (HAND2) in adipogenesis. Methods: Human white adipose tissue (WAT) were collected in a cross-sectional study of 318 individuals. In vitro, for mechanistic experiments we used primary adipocytes from human and mice as well as human multipotent adipose derived stem (hMADS) cells. Gene silencing was performed using siRNA or genetic inactivation in primary adipocytes from LoxP mouse models with Cre-encoding mRNA. Adipogenesis efficiency was measured by OilRedO staining, qPCR and microarray. A combinatorial RNASeq approach was used to identify gene clusters regulated by HAND2. In vivo, we created a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter (HAND2AdipoqCRE). Results: We found that HAND2 is an obesity-linked white adipocyte transcription factor regulated by glucocorticoids that was required but insufficient for adipocyte differentiation in vitro. In a large cohort of humans with obesity, WAT HAND2 expression was correlated to body-mass-index (BMI). The HAND2 gene was enriched in white adipocytes compared to brown, induced early in differentiation and responded to DEX, a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in hMADS or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by GCs via GR in vitro and in vivo. Furthermore, we identified gene clusters indirectly regulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that Hand2 was required at stages prior to Adipoq expression. Conclusion: In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in human and mice.
2021-02-26 | GSE148699 | GEO