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Caspase-1 is a member of the intracellular cysteine protease family that mediates inflammation through the activation of the cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). As mice lacking IL-18 become obese and insulin resistant, and both IL-18 and IL-1β have a role in overall energy balance, we sought to determine whether caspase-1 deficiency also causes obesity. Male and female caspase-1-deficient (caspase-1−/−) and control (wild-type (WT)) mice were fed either a high-fat (HF, 45% of kcal) or a low-fat (LF, 10% of kcal) synthetic diet starting at 6 weeks of age. Caspase-1−/− mice maintained lower but detectable levels of IL-18 compared with WT mice. Plasma IL-1β levels were below the detection limit for both KO and WT mice. Male caspase-1−/− mice gained extra fat mass by 16 weeks on the HF diet, but not until 40 weeks on the LF diet. Female capase-1−/− mice gained more fat by 28 weeks but only on the HF diet. These data indicate that caspase-1−/− mice develop obesity with an age and sex-dependent differences, and only male mice display obesity on LF diet. Overall, this study suggests that the lower level of IL-18 in caspase-1−/− mice might be causing obesity development similarly to IL-18-deficient mice. [ABSTRACT FROM AUTHOR]