Selective targeting of visceral adiposity by polycation nanomedicine
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA862525 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20653314_1.fastq.gz | Fastqsanger.gz | |||
| SRR20653314_2.fastq.gz | Fastqsanger.gz | |||
| SRR20653315_1.fastq.gz | Fastqsanger.gz | |||
| SRR20653315_2.fastq.gz | Fastqsanger.gz | |||
| SRR20653316_1.fastq.gz | Fastqsanger.gz |
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Project description:Obesity is a pandemic health problem with poor solutions, especially for targeted treatment. Here we develop a polycation-based nanomedicine to selectively target visceral adiposity, the more metabolically detrimental and manipulation-resistant fat. We demonstrated that the polycationic polymer polyamidoamine (PAMAM) generation 3 (P-G3) was specifically enriched in the visceral fat due to its high charge density when delivered intraperitoneally. Moreover, P-G3 treatment of obese mice inhibited visceral adiposity, increased energy expenditure, prevented obesity, and alleviated the associated metabolic dysfunctions. In vitro adipogenesis models and single-cell RNA sequencing (scRNA-seq) revealed that P-G3 paradoxically uncouples the defining function of adipocyte - lipid synthesis and storage - from adipocyte development to create unique “dwarf” adipocytes that possess normal adipocyte functions but are deficient in hypertrophic growth at least through synergistically modulating NAD and mTOR pathways. The visceral fat distribution of P-G3 was further enhanced by modifying P-G3 with cholesterol to form lipophilic nanoparticles, which were also effective in treating obesity. Our study highlights an unexpected strategy to tackle visceral adiposity and champions a new direction of exploring cationic nanomaterials for treating metabolic diseases.
2022-09-19 | GSE209819 | GEO
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:Accumulation of visceral fat around internal organs, is a strong risk predictor for cardiometabolic disease. Although fat deposition at distinct anatomical sites is influenced by genetic factors their functional mechanism remains poorly understood. Here, we show ENPP6 as a neural determinant of selectively visceral adiposity. Through dual-energy X-ray absorptiometry (DXA) body composition analysis in 1,301 individuals from the isolated population of Orkney, we identified low-frequency variants at 4q35.1 associated with a reduction of DXA fat distribution (rs144607341/rs17583822, P = 2.7 x 10-10/ 2.0 x 10-9). A decrease in abdominal fat% and visceral fat mediate the altered fat distribution. We replicated these associations in 3,219 Icelanders for abdominal fat mass by computerized-tomography (P = 0.02/ 0.003). Rs17583822 and nearby SNPs mapped within the second intron of ENPP6 that is predicted as a site of transcriptional regulator. We observed close proximity of these variants and the promoter of ENPP6 by 3D-fluorescent in situ hybridization (3D-FISH) in human neurons but not in adipocytes, supporting a regulatory relationship in the brain. Moreover, enriched 5C interactions across the TAD containing ENPP6 and STOX2 in neurons, especially between a STOX2 intronic region and ENPP6 introns one and two, suggests that this region is more compact in cells where both genes are active and they both share cis regulatory elements. Enpp6 knockout mice exhibited reduced visceral fat, improved glucose tolerance, resistance to fatty liver, and maintenance of energy-dissipation of white fat depots when exposed to high fat diet. Our results reveal ENPP6 as a potential therapeutic target for selective accumulation of high-risk visceral obesity and diabetes.
2018-12-21 | GSE108403 | GEO
Project description:ENPP6 as a neural regulator of visceral adiposity
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Project description:We profiled gene expression in peripheral blood cells from 17 obese patients by microarray analysis and revealed that visceral fat adiposity impact on gene expression profile in peripheral blood cells compared to subcutaneous fat accumulation.
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Project description:Adipocyte serine uptake curbs ROS generation and visceral adiposity
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Project description:Adipocyte serine uptake curbs ROS generation and visceral adiposity [Zebrafish]
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Project description:Adipocyte serine uptake curbs ROS generation and visceral adiposity [Human]
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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, where human primary preadipocytes were isolated from liposuction aspirate and differentiated. At day 7 of differentiation, cells were treated with BMS-466442 or vehicle (DMSO) for 24 hours. After incubation, cells were lysed, and RNA was purified, DNase treated, and the RNA integrity number was checked. Subsequently, cDNA libraries were generated via the TruSeq Stranded mRNA Library Prep kit and sequenced by Illumina Hiseq 4000.
2020-01-19 | GSE135155 | 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. 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