Selective targeting of visceral adiposity by polycation nanomedicine
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE209819 | GEO | 2022/09/19
REPOSITORIES: GEO
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Project description:Maternal obesity is linked with increased adverse outcomes for mother and fetus. However, the metabolic impact of excessive fat accumulation within the altered hormonal context of pregnancy is not well understood. We used a murine model of obesity, the high fat diet-fed C57BL/6J mouse to determine adipose tissue-mediated molecular mechanisms driving metabolic dysfunction throughout pregnancy. Remarkably, obese mice exhibited a normalization of visceral fat accumulation at late-stage pregnancy (-53%, P<0.001 E18.5) to achieve levels comparable in mass (per gram of body weight) to that of non pregnant, control diet fed mice. Moreover, whilst obese pregnant mice showed a marked glucose intolerance and apparent insulin resistance at mid-stage pregnancy (E14.5), glucose homeostasis converged with that of lean pregnant mice at late-stage pregnancy, suggesting an unexpected amelioration of the worsening metabolic dysfunction in obese pregnant mice. Transcriptomic analysis of the late-stage visceral fat indicated reduced de novo lipogenic drive (Me1, Fasn, Scd1, Dgat2), retinol metabolism (Rdh11, Rbp4) and inflammation (Mcp1, Tnfα) in obese pregnant mice that was confirmed functionally by their lower adipose proinflammatory macrophage density. Elevated expression of estrogen receptor a (ERα) in visceral adipose tissue was identified as potential unifying mechanism for the transcriptional changes and reduced adiposity of late stage obese pregnancy. Support for a role for ERα was provided by experiments showing that the ERα selective agonist PPT suppressed lipogenesis in primary mouse adipocytes and suppressed Me1, Fasn, SCD1 and Dgat2 mRNA levels in mature female human ChubS7 clonal fat cells. Our data reveal a novel role for elevated visceral adipocyte estrogen signaling as a protective mechanism against visceral fat hypertrophy and inflammation in late pregnancy. Pregnant high fat, pregnant control fat, non pregnant high fat, non pregnant control fat. Five biologial replictes each (20 samples).
2013-12-31 | E-GEOD-48811 | biostudies-arrayexpress
Project description:Obesity, and visceral adiposity in particular, increases the risk of common metabolic diseases, including type 2 diabetes, cardiovascular disease, and several forms of cancer. However, the molecular mechanisms responsible for regional fat storage remain poorly characterized, preventing therapeutic innovation. We here applied a systematic genome-wide screen and translational approach, and discovered a novel role for the adipocyte-expressed neutral amino acid transporter SLC7A10/ASC-1 in the regulation of visceral adiposity. Among 65 genes showing both adipose depot-dependent and fat loss-dependent expression, 27 genes further showed significant correlations with waist-to-hip (WHR) ratio adjusted for BMI. Among these ASC-1 was expressed at the highest level in isolated visceral adipocytes. Further, we found decreased ASC-1 mRNA in visceral, and not subcutaneous adipose tissue, in carriers of the KLF14 type 2 diabetes risk allele compared to the protective allele. By profiling amino acid fluxes during adipocyte differentiation in vitro, we found that ASC-1 inhibition by a selective inhibitor decreased adipocyte uptake particularly of serine in mature adipocytes. Interestingly, radiometric amino acid uptake assays showed ASC-1 dependent uptake of the serine D-enantiomere. Using primary human and murine adipocyte models, we uncovered marked effects of inhibiting ASC-1 on mitochondrial respiratory capacity (within hours) and lipid accumulation (within days). Finally, Asc-1 knockout (KO) zebrafish had increased body weight and adipocyte enlargement upon eight-week overfeeding compared to wild-type (WT) fish. RNA sequencing data from zebrafish adipose tissue showed up-regulation of genes involved in fatty acid and lipid metabolism in the ASC-1 KOs, consistent with the increased lipid accumulation in the inhibitor-treated cell models. Additionally, duox, an enzyme involved in ROS generation, showed higher expression in the KOs compared to the WTs. Importantly, we confirmed increased reactive oxygen species (ROS) generation (within minutes and within hours) when inhibiting ASC-1 in our in vitro cell models. Our study points to increased ROS generation and reduced mitochondrial respiratory capacity as central early mechanisms in development of visceral adiposity, and a role for adipocyte D-serine transport via ASC-1 in these processes. Enhancing ASC-1 expression and/or activity in adipocytes, likely through primary effects on one-carbon metabolism and redox balance, is a promising therapeutic strategy for reducing visceral adiposity and related diseases.
2021-01-30 | GSE134733 | GEO
Project description:Obesity is characterized by the excess of body fat leading to impaired health. Abdominal fat is particularly harmful and is associated with cardiovascular and metabolic diseases and cancer. In contrast, subcutaneous fat is generally considered less detrimental. The mechanisms that establish the cellular characteristics of these distinct fat types in humans are not fully understood. Here, we explored whether differences of their gene regulatory mechanisms can be investigated in vitro. For this purpose, we in vitro differentiated human visceral and subcutaneous pre-adipocytes into mature adipocytes and obtained their gene expression profiles and genome-wide H3K4me3, H3K9me3 and H3K27ac patterns. Subsequently, we compared those data with public gene expression data from visceral and subcutaneous fat tissues. We found that the in vitro differentiated adipocytes show significant differences in their transcriptional landscapes, which correlate with biological pathways that are characteristic for visceral and subcutaneous fat tissues, respectively. Unexpectedly, visceral adipocyte enhancers are rich on motifs for transcription factors involved in the Hippo-YAP pathway, cell growth and inflammation, which are not typically associated with adipocyte function. In contrast, enhancers of subcutaneous adipocytes show enrichment of motifs for common adipogenic transcription factors, such as C/EBP, NFI and PPARgamma, implicating substantially disparate gene regulatory networks in visceral and subcutaneous adipocytes. Consistent with the role in obesity, predominantly the histone modification pattern of visceral adipocytes is linked to obesity-associated diseases. Thus, this work suggests that the properties of visceral and subcutaneous fat tissues can be studied in vitro and provides preliminary insights into their gene regulatory processes.
2018-06-30 | GSE102638 | GEO
Project description:Maternal obesity is linked with increased adverse outcomes for mother and fetus. However, the metabolic impact of excessive fat accumulation within the altered hormonal context of pregnancy is not well understood. We used a murine model of obesity, the high fat diet-fed C57BL/6J mouse to determine adipose tissue-mediated molecular mechanisms driving metabolic dysfunction throughout pregnancy. Remarkably, obese mice exhibited a normalization of visceral fat accumulation at late-stage pregnancy (-53%, P<0.001 E18.5) to achieve levels comparable in mass (per gram of body weight) to that of non pregnant, control diet fed mice. Moreover, whilst obese pregnant mice showed a marked glucose intolerance and apparent insulin resistance at mid-stage pregnancy (E14.5), glucose homeostasis converged with that of lean pregnant mice at late-stage pregnancy, suggesting an unexpected amelioration of the worsening metabolic dysfunction in obese pregnant mice. Transcriptomic analysis of the late-stage visceral fat indicated reduced de novo lipogenic drive (Me1, Fasn, Scd1, Dgat2), retinol metabolism (Rdh11, Rbp4) and inflammation (Mcp1, Tnfα) in obese pregnant mice that was confirmed functionally by their lower adipose proinflammatory macrophage density. Elevated expression of estrogen receptor a (ERα) in visceral adipose tissue was identified as potential unifying mechanism for the transcriptional changes and reduced adiposity of late stage obese pregnancy. Support for a role for ERα was provided by experiments showing that the ERα selective agonist PPT suppressed lipogenesis in primary mouse adipocytes and suppressed Me1, Fasn, SCD1 and Dgat2 mRNA levels in mature female human ChubS7 clonal fat cells. Our data reveal a novel role for elevated visceral adipocyte estrogen signaling as a protective mechanism against visceral fat hypertrophy and inflammation in late pregnancy.
2013-12-31 | GSE48811 | GEO
Project description:Visceral fat (VF) and subcutaneous fat (SF) are developmentally different tissues with different gene expression. Islet-1 (ISL1), a LIM-homeobox transcription factor with important developmental and regulatory function in islet, neural, and cardiac tissue, is virtually absent in SF but substantially expressed in the stromovascular [preadipocyte containing] fraction of VF; expression correlates negatively with adiposity in rodents and man. ISL1 expression is transiently increased in 3T3-L1 preadipocytes during early differentiation, suggesting a functional role. To examine the role of ISL1 in adipogenesis, we tested whether retroviral overexpression of ISL1 in 3T3-L1 preadipocytes affected their ability to differentiate into mature adipocytes. Terminal differentiation was assessed by Oil Red O [lipid droplet] staining and by immunoblot detection of adipocyte marker proteins, including aP2 and GLUT4. ISL1 significantly inhibited lipid droplet formation, reduced lipid accumulation (about 80% inhibition, p<0.05), and substantially inhibited aP2 and GLUT4 expression. ISL1 did not inhibit expression of C/EBPb and C/EBPd after induction of differentiation, but reduced PPARg and C/EBPa by >50% at both mRNA and protein level. In addition, the PPARg agonist, rosiglitazone, substantially rescued ISL1 inhibited adipogenesis in the absence of exogenous PPARg, and fully rescued in the presence of exogenous PPARg. In summary, ISL1 overexpression inhibited fat droplet formation, lipid accumulation, and adipocyte-specific gene expression; there was accompanying inhibition of C/EBPa, PPARg and downstream gene expression. We conclude that ISL1 overexpression inhibited adipocyte differentiation by inhibition of PPARg regulated gene expression. As abdominal obesity strongly correlates with insulin resistance, and cardiovascular risk, ISL1 up-regulation may impact abdominal obesity and its concomitant metabolic derangements. Total cellular RNA was isolated from 3T3-L1 cells expressing Flag-ISL1 or not at 48 h following treatment with differentiation cocktail. Individual RNA from biological triplicates was used for microarray analysis.
2012-09-05 | E-GEOD-40565 | biostudies-arrayexpress
Project description:White adipose tissue (WAT) distribution is sex dependent. Adipocyte hyperplasia contributes to WAT distribution in mice driven by cues in the tissue microenvironment, with females displaying hyperplasia in subcutaneous and visceral WAT, while males and ovariectomized females have visceral WAT (VWAT)-specific hyperplasia. However, the mechanism underlying sex-specific hyperplasia remains elusive. Here, transcriptome analysis in female mice shows that high-fat diet (HFD) induces estrogen signaling in adipocyte precursor cells (APCs). Analysis of APCs throughout the estrous cycle demonstrates increased proliferation only when proestrus (high estrogen) coincides with the onset of HFD feeding. We further show that estrogen receptor α (ERα) is required for this proliferation and that estradiol treatment at the onset of HFD feeding is sufficient to drive it. This estrous influence on APC proliferation leads to increased obesity driven by adipocyte hyperplasia. These data indicate that estrogen drives ERα-dependent obesogenic adipocyte hyperplasia in females, exacerbating obesity and contributing to the differential fat distribution between the sexes.
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Project description:Adipocyte-specific expression of Na,K-ATPase signaling antagonist, NaKtide, has been shown to ameliorate the pathophysiological consequences of obesity and improve diseased phenotype. Recent studies have established that the release of adipocytokines and other bioactive mediators in obesity contributes to neurodegeneration. This study utilizes a mechanistic approach and characterizes the hippocampal transcriptome in comparison with transcriptomic changes in liver, visceral and subcutaneous adipose tissue. RNAseq analysis in high fat diet fed transgenic mice showed large scale differential gene expression as well as modulation of several biological pathways in hippocampus, liver, visceral and subcutaneous adipose tissue, which were attenuated by doxycycline induced adipocyte specific NaKtide expression.
2021-11-10 | GSE164294 | GEO
Project description:Time-course analysis of adipocyte gene expression profiles response to high fat diet. The hypothesis tested in the present study was that in diet-induced obesity, early activation of TLR-mediated inflammatory signaling cascades by CD antigen genes, leads to increased expression of pro-inflammatory cytokines and chemokines, resulting in chronic low-grade inflammation. Early changes in collagen genes may trigger the accumulation of ECM components, promoting fibrosis in the later stages of diet-induced obesity. New therapeutic approaches targeting visceral adipose tissue genes altered early by HFD feeding may help ameliorate the deleterious effects of a diet-induced obesity. Total RNA obtained from isolated epididymal and mesenteric adipose tissue of C57BL/6J mice fed normal diet or high fat diet for 2, 4, 8, 20 and 24weeks
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Project description:Regulation of organismal homeostasis in response to nutrient availability is a vital physiological process that involves inter-organ communication. Understanding the mechanisms controlling systemic cross talk for maintenance of metabolic health is critical to counteract diet-induced obesity. Here, we show that cardiac-derived transforming growth factor beta 1 (TGF-b1) protects against weight gain and glucose intolerance in mice subjected to high-fat diet. Secretion of TGF-b1 by cardiomyocytes correlates with bioavailability of this factor in circulation. TGF-b1 prevents adipose tissue inflammation independent of body weight and glucose metabolism phenotypes, suggesting protection from adipocyte dysfunction-driven immune cell recruitment. TGF-b1 alters gene expression programs in white adipocytes, favoring their thermogenic fate and consequently increasing their mitochondrial oxygen consumption rates. Ultimately, subcutaneous and visceral white adipose tissue from heart-specific TGF-b1 transgenic mice fail to undergo cellular hypertrophy, leading to reduced overall adiposity during high-fat feeding. Thus, TGF-b1 is a critical mediator of heart-fat communication for regulation of systemic metabolism.
2021-11-03 | GSE179102 | GEO