Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m(2)], but their contribution to common obesity (BMI ≥ 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (β = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (β = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.

The role of obesity in the development of dorsopathies is still unclear. In this study, we assessed the associations between body mass index (BMI) and several dorsopathies including intervertebral disc degeneration (IVDD), low back pain (LBP), and sciatica by using the Mendelian randomization method. We also assessed the effect of several obesity-related traits on the same outcomes. Single-nucleotide polymorphisms associated with the exposures are extracted from summary-level datasets of previously published genome-wide association studies. Summary-level results of IVDD, LBP, and sciatica were from FinnGen. In our univariable Mendelian randomization analysis, BMI is significantly associated with increased risks of all dorsopathies including sciatica (OR = 1.33, 95% CI, 1.21–1.47, p = 5.19 × 10-9), LBP (OR = 1.28, 95% CI, 1.18–1.39, p = 6.60 × 10-9), and IVDD (OR = 1.23, 95% CI, 1.14–1.32, p = 2.48 × 10-8). Waist circumference, hip circumference, whole-body fat mass, fat-free mass, and fat percentage, but not waist–hip ratio, were causally associated with increased risks of IVDD and sciatica. Higher hip circumference, whole-body fat mass, fat-free mass, and fat percentage increased the risk of LBP. However, only whole-body fat-free mass remained to have a significant association with the risk of IVDD after adjusting for BMI with an odds ratio of 1.57 (95% CI, 1.32–1.86, p = 2.47 × 10-7). Proportions of BMI’s effect on IVDD, sciatica, and LBP mediated by leisure sedentary behavior were 41.4% (95% CI, 21.8%, 64.8%), 33.8% (95% CI, 17.5%, 53.4%), and 49.7% (95% CI, 29.4%, 73.5%), respectively. This study provides evidence that high BMI has causal associations with risks of various dorsopathies. Weight control is a good measure to prevent the development of dorsopathies, especially in the obese population.

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Type 2 diabetes mellitus (T2DM) affects millions of people and is linked with obesity and lipid accumulation in peripheral tissues. increased lipid handling and lipotoxicity in insulin producing β-cells may contribute to β-cell dysfunction in T2DM. The vascular endothelial growth factor (VEGF)-B regulates uptake and transcytosis of long-chain fatty acids over the endothelium to tissues such as heart and skeletal muscle. Systemic inhibition of VeGf-B signaling prevents tissue lipid accumulation, improves insulin sensitivity and glucose tolerance, as well as reduces pancreatic islet triglyceride content, under T2DM conditions. To date, the role of local VEGF-B signaling in pancreatic islet physiology and in the regulation of fatty acid trans-endothelial transport in pancreatic islet is unknown. to address these questions, we have generated a mouse strain where VeGf-B is selectively depleted in β-cells, and assessed glucose homeostasis, β-cell function and islet lipid content under both normal and high-fat diet feeding conditions. We found that Vegfb was ubiquitously expressed throughout the pancreas, and that β-cell Vegfb deletion resulted in increased insulin gene expression. However, glucose homeostasis and islet lipid uptake remained unaffected by β-cell VEGF-B deficiency.