ENPP6 as a neural regulator of visceral adiposity

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. 5C oligonucleotides were designed around EcoRI restriction sites following an alternative scheme