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ENPP6 as a neural regulator of visceral adiposity

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE108403 | GEO | 2018/12/21

REPOSITORIES: GEO

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Project description:Objective: Abdominal adiposity is strongly associated with diabetic and cardiovascular comorbidities. The long non-coding RNA HOTAIR (HOX Transcript Antisense Intergenic RNA) is an important epigenetic regulator, with fat depot-specific expression between abdominal subcutaneous adipose tissue (SAT) and gluteal SAT. HOTAIR locates closely with HOXC13, known to strongly associated with human fat distribution. Here, we examined the phenotypic effects of HOTAIR overexpression on abdominal adipogenesis, and hypothesized that HOTAIR-mediated DNA methylation is correlated with transcriptome changes, leading to the regulation of specific genes and the functional pathways. Methods: The expression level of HOTAIR was compared among different fat-depots collected from six healthy, five severe obese, and five uremic subjects, and was correlated with dual-energy x-ray absorptiometry (DXA) defined regional adiposity. The human immortalized preadipocyte was used to assess the phenotypic effects of HOTAIR overexpression on abdominal adipogenesis. The integrative analysis of reduced representation bisulfite sequencing (RRBS) and RNA-sequencing was performed to identify putative genes that are epigenetically regulated by HOTAIR, and the associated signaling pathways. HOTAIR-repressed genes were further validated using RNA/chromatin immunoprecipitation with real-time qPCR and correlated with human body fat distribution. Results: We found that the expression of HOTAIR was high in gluteal SAT, and low in arm/abdominal SAT and visceral (omental) adipose tissue. It could be aberrantly increased in uremic arm SAT. Notably, in severe obese subjects we found that HOTAIR is lowly expressed in abdominal SAT correlating with a higher abdominal adiposity, whereas in uremic patients HOTAIR is highly expressed in arm SAT correlating with lower arm adiposity. HOTAIR overexpression in human immortalized abdominal preadipocyte remarkably suppresses the in vitro adipogenesis. Overall the differentially methylated genes were functionally enriched for nervous system development. We specifically identified 10 HOTAIR-mediated genes showing strong changes of DNA methylation associated with gene expression during abdominal adipogenesis, suggesting potential epigenetic regulation. Two HOTAIR-repressed genes, SLITRK4 and PITPNC1, were further highlighted and validated; presenting an obesity-driven fat-depot specific expression pattern positively correlated with the central body fat distribution. Conclusions: Our study indicated that HOTAIR is an important regulator for abdominal adipogenesis via intricate DNA methylation likely to associate with transcriptional regulation of specific genes, such as SLITRK4 and PITPNC1.

Project description:Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of liver disease affecting 20-30% of the population in developed countries. NAFLD is strongly associated with abdominal obesity and is recognized as the hepatic manifestation of the metabolic syndrome. In a subgroup of patients with NAFLD inflammation and fibrosis develops, this so-called Non-Alcoholic Steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma. A multi-hit hypothesis has been proposed in which during the first “hit” fat accumulation occurs in hepatocytes from excessive delivery of fatty acids from adipose tissue, in addition there is an imbalance in lipid synthesis and export. However, the reason why fat accumulation is subsequently followed by inflammation and fibrosis in some patients is poorly understood. We studied the role of inflammatory processes in visceral and subcutaneous fat at the transcriptional level using microarray in bariatric patients from whom the liver histology was available. Patients scheduled for bariatric surgery were recruited in two centers (Pretoria/South-Africa and Antwerpen/Belgium). At the time of the procedure, tissue samples of the visceral and subcutaneous fat were taken for molecular analysis as well as liver tissue for histology, also full biochemical data was collected. Patients were grouped according histology: group I (<5% steatosis), group II (NAFLD, 30-50% steatosis), group III (NASH) and group IV (NASH + fibrosis F2-F3). The following samples were used for microarray (number of 'patients' respectively for stages I-II-III-IV): visceral fat (9-7-7-5), subcutaneous fat (6-6-6-5). Microarrays were run in two batches (15xxx versus 17xxx CEL file samples; indicated in the description field). Samples from two patients (FN61; FN76) were put twice on array (15078+17881; 15064+17877) to verify and exclude batch effects. Please note that, due to technical repeats with two patient samples, the number of 'visceral fat samples' for stages I-II-III-IV is 10-7-8-5.

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ENPP6 as a neural regulator of visceral adiposity

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