Severe obesity, high inflammation, insulin resistance with risks of all-cause mortality and all-site cancers, and potential modification by healthy lifestyles.

Severe obesity is often associated with inflammation and insulin resistance (IR), which expected to increase the risks of mortality and cancers. However, this relationship remains controversial, and it's unclear whether healthy lifestyles can mitigate these risks. The independent and joint associations of severe obesity (body mass index ≥ 35 m/kg), inflammation (C-reactive protein > 10 mg/L and systemic inflammation markers > 9th decile), and IR surrogates with the risks of all-cause mortality and all-site cancers, were evaluated in 163,008 participants from the UK Biobank cohort. Further analyses were conducted to investigate how these associations were modified by lifestyle. During a median follow-up of 11.0 years, we identified 8844 deaths and 20,944 cancer cases. Severe obesity, inflammation and IR were each independently associated with increased risks of all-cause mortality [HRs(95%CIs) 1.24(1.17-1.30), 1.63(1.55-1.72) and 1.11(1.05-1.17)] and all-site cancers [1.06(1.02-1.10), 1.14(1.10-1.19) and 1.02(0.99-1.06)]. Joint analyses revealed significantly elevated risks of all-cause mortality and all-site cancers due to interaction between severe obesity, inflammation and IR, with the highest HRs(95%CIs) of 1.88(1.67-2.11) and 1.20(1.08-1.34), respectively. Further analyses showed stronger interaction between severe obesity, inflammation, IR and lifestyles, with similar associations observed in both males and females. Additionally, compared with unfavorable lifestyles, favorable lifestyles attenuated the risks of both all-cause mortality [the highest HRs(95%CIs) 2.35(1.75-3.15) vs. 3.72(2.86-4.84) for favorable vs. unfavorable lifestyles] and all-site cancers [1.16(0.89-1.53) vs. 1.63(1.26-2.10)]. Severe obesity interacts with inflammation and IR to exacerbate the risks of all-cause mortality and all-site cancers. Nonetheless, adherence to healthy lifestyles is recommended to mitigate these increased risks.