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Background Cardiorespiratory fitness may moderate the association between obesity and all-cause mortality (ie, the "fat-but-fit" hypothesis), but unaddressed sources of bias are a concern. Methods and Results Cardiorespiratory fitness was estimated as watts per kilogram from a submaximal bicycle test in 77 169 men and women from the UK Biobank cohort and combined with World Health Organization standard body mass index categories, yielding 9 unique fitness-fatness combinations. We also formed fitness-fatness combinations based on bioimpedance as a direct measure of body composition. All-cause mortality was ascertained from death registries. Multivariable-adjusted Cox regression models were used to estimate hazard ratios and 95% CIs. We examined the association between fitness-fatness combinations and all-cause mortality in models with progressively more conservative approaches for accounting for reverse causation, misclassification of body composition, and confounding. Over a median follow-up of 7.7 years, 1731 participants died. In our base model, unfit men and women had higher risk of premature mortality irrespective of levels of adiposity, compared with the normal weight-fit reference. This pattern was attenuated but maintained with more conservative approaches in men, but not in women. In analysis stratified by sex and excluding individuals with prevalent major chronic disease and short follow-up and using direct measures of body composition, mortality risk was 1.78 (95% CI, 1.17-2.71) times higher in unfit-obese men but not higher in obese-fit men (0.94 [95% CI, 0.60-1.48]). In contrast, there was no increased risk in obese-unfit women (1.09 [95% CI, 0.44-1.05]) as compared with the reference. Conclusions Cardiorespiratory fitness modified the association between obesity and mortality in men, but this pattern appeared susceptible to biases in women.

Objective: To examine the combined and stratified associations of physical activity and adiposity measures, modelled as body mass index (BMI), abdominal adiposity (waist circumference), and body fat percentage (BF) with all-cause mortality., Patients and Methods: Using the UK Biobank cohort, we extracted quintiles of self-reported weekly physical activity. Categories of measured BMI, waist circumference, and BF were generated. Joint associations between physical activity-adiposity categories and mortality were examined using Cox proportional hazards models adjusted for demographic, behavioral, and clinical covariates. Physical activity-mortality associations were also examined within adiposity strata. Participants were followed from baseline (2006 to 2010) through January 31, 2018., Results: A total of 295,917 participants (median follow-up, 8.9 years, during which 6684 deaths occurred) were included. High physical activity was associated with lower risk of premature mortality in all strata of adiposity except for those with BMI ≥35 kg/m 2 . Highest risk (HR, 1.54; 95% CI; 1.33 to 1.79) was observed in individuals with low physical activity and high BF as compared with the high physical activity-low BF referent. High physical activity attenuated the risk of high adiposity when using BF (HR, 1.24; 95% CI; 1.04 to 1.49), but the association was weaker with BMI (HR, 1.45; 95% CI; 1.21 to 1.73). Physical activity also attenuated the association between mortality and high waist circumference., Conclusion: Low physical activity and adiposity were both associated with a higher risk of premature mortality, but high physical activity attenuated the increased risk with adiposity irrespective of adiposity metric, except in those with a BMI ≥35 kg/m 2 ., (Copyright © 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)