ENPP6 as a neural regulator of visceral adiposity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA427135 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6409990.fastq.gz | Fastqsanger.gz | |||
| SRR6409991.fastq.gz | Fastqsanger.gz | |||
| SRR6409988.fastq.gz | Fastqsanger.gz | |||
| SRR6409989.fastq.gz | Fastqsanger.gz |
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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: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.
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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, 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.
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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:<p>The Health Aging and Body Composition (Health ABC) Study is a NIA-sponsored cohort study of the factors that contribute to
incident disability and the decline in function of healthier older persons, with a particular emphasis on changes in body composition
in old age. Between 4/15/97 and 6/5/98 the Health ABC study has recruited 3,075 70-79 year old community-dwelling adults
(41% African-American), who were initially free of mobility and activities of daily living disability. The key components of
Health ABC include a baseline exam, annual follow-up clinical exams, and phone contacts every 6 months to identify major health
events and document functional status between clinic visits.</p>
<p>The core yearly examination for HEALTH ABC includes measurement of body composition by dual energy x-ray absorptio-metry (DXA),
walking ability, strength, an interview that includes self-report of limitations, and a medication survey, weight. At baseline, visceral
adiposity was measured by computerized tomography (CT). Provision has been made for banking of blood specimens and extracted DNA
(HealthABC repository). The overall goal of this project is to identify genetic determinants of visceral adiposity. Genetic samples
from 2932 unrelated participants were evaluated with a genome-wide scan.</p>
| phs000169 | dbGaP