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Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10−09), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin βE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.

Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein-coupled receptors (CALCR, MC4R, GIPR, GPR151, and GPR75). Protein-truncating variants in GPR75 were observed in ~4/10,000 sequenced individuals and were associated with 1.8 kilograms per square meter lower BMI and 54% lower odds of obesity in the heterozygous state. Knock out of Gpr75 in mice resulted in resistance to weight gain and improved glycemic control in a high-fat diet model. Inhibition of GPR75 may provide a therapeutic strategy for obesity.

Additional file 1: Table S1. Physiological endpoint characteristics of STZ-HFD-induced murine diabetes. Table S2. Endpoint M-Mode echocardiography for assessing cardiac systolic function in murine diabetes. Table S3. Organ weights. Table S4. Flow cytometry antibody panel utilised in whole blood from mice. Table S5. Flow cytometry antibody panel utilised in myocardium from mice. Figure S1. (A) Representative images of transmitral annular blood flow via Doppler echocardiography. Quantified Doppler flow; (B) Anaesthetised heart rate (HR), (C) peak E-wave velocity, (D) A-wave velocity (E) E:A ratio, (F) deceleration time (DT) and (G) isovolumic relaxation time (IVRT). (H) Shows representative images for tissue Doppler echocardiography, quantified in figures I-L. (I) Peak e' velocity (P=0.054), (J) peak a' velocity (P = 0.072), (K) e':a' ratio, (L) E:e' ratio. ND = non-diabetic, DM = diabetes mellitus. Data presented as mean ± SEM and individual data points, and analysed using an unpaired t-test. Statistical significance was assumed at P

Introduction and Objectives: The Oxford Foot Model (OFM) [1] was developed to get accurate measurement of foot movement during gait as the bone pin method [2] is not practical for most clinical situations. It has been validated in adults [3] and children [4]. However, since barefoot walking on a treadmill is not recommended there is a question over whether the OFM can be usefully applied in facilities such as the Motek CAREN (Computer Assisted Rehabilitation Environment - motekmedical.com). Consequently, there is an interest to see if applying OFM markers to shoes can give useful results when measuring human walking on treadmills. This study looks at the differences in measurements using the OFM between walking over-ground (barefoot and with shoes) and on a treadmill (with shoes). Methods: Nine boys (mean age 13.5±0.5yrs, height 1.59±0.09m, mass 47.8±8.3kg) were recruited. Retro-reflective markers were attached bilaterally following the Plug-in-Gait lower limb and OFM models. The over-ground (barefoot and with shoes) trials were recorded in a standard gait laboratory (12 camera Vicon T-Series). Barefoot trials were performed first to minimise the need to reattach markers. The treadmill walking trials were recorded in the CAREN immediately after the over-ground trials (12 camera Vicon Bonita10). The treadmill speed was set to match the speed of over-ground walking in the gait laboratory. Gait events were determined from force plate contacts. All the boys wore light indoor training shoes. Data was captured using Vicon Nexus 1.8.5 and processed using Plug in Gait and OFM models in Nexus 2.1. Results: There was no difference in ankle kinematics between over-ground (barefoot and with shoes) and on a treadmill (with shoes). Although Forefoot-Hindfoot angles were comparable to the literature in the barefoot condition, this was not the case with shoes (Table 1). Barefoot, there was a steady dorsiflexing motion throughout stance until push off which was signified by a rapid plantar-flexing motion. With shoes on, the same model segments show rapid dorsiflexion, then plantar flexion during early stance followed by neutral position held until push-off. Conclusion: Reinschmidt and colleagues [2] reported that the shape of the calcaneal motion curves was similar for shoe mounted markers and bone markers, but that the shoe-mounted markers overestimated joint angles. In this study, the shape of the curves was quite different.