Relationships between body fat distribution and metabolic syndrome traits and outcomes: a Mendelian Randomization study

Background Obesity is a complex, multifactorial disease associated with substantial morbidity and mortality worldwide. Although overweight and obesity are frequently assessed using BMI, many epidemiological studies have shown links between body fat distribution and obesity-related outcomes. This study examined the relationships between body fat distribution and metabolic syndrome traits using Mendelian Randomization (MR). Methods and Findings Genetic variants associated with visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), and gluteofemoral adipose tissue (GFAT), as well as their relative ratios, were identified from a genome wide association study (GWAS) performed among participants of the United Kingdom BioBank. GWAS summary statistics for traits and outcomes related to metabolic syndrome were obtained from the IEU Open GWAS Project. Two-sample MR and multivariable MR (MVMR) controlling for BMI were performed to examine the relationships between each body fat measure and ratio with the selected outcomes. Increases in absolute GFAT were associated with a protective cardiometabolic profile, including lower low density lipoprotein cholesterol (β: -0.19, [95% CI: -0.28, -0.10], p < 0.001), higher high density lipoprotein cholesterol (β: 0.23, [95% CI: 0.03, 0.43], p = 0.025), lower triglycerides (β: - 0.28, [95% CI: -0.45, -0.10], p = 0.0021), and decreased systolic (β: -1.65, [95% CI: -2.69, -0.61], p = 0.0019) and diastolic blood pressures (β: -0.95, [95% CI: -1.65, -0.25], p = 0.0075). These relationships were largely maintained when controlling for BMI in MVMR analyses. Decreases in relative GFAT were linked with a worse cardiometabolic profile, with higher levels of detrimental lipids and increases in systolic and diastolic blood pressures. Conclusion An MR analysis of ASAT, GFAT, and VAT fat depots and their relative ratios with metabolic syndrome related traits and outcomes revealed that increased absolute and relative GFAT were associated with a favorable cardiometabolic profile independently of BMI. These associations highlight the importance of body fat distribution in obesity and supports developing more precise means to categorize obesity beyond BMI.