Mlkl−/− and Mlkl+/− mice are resistant to diet-induced obesity. (A) Schematic representation of the experimental design. Male mice were fed CD (WT, Mlkl−/− or Mlkl+/−) or HFHFrHC diet (WT, Mlkl−/− or Mlkl+/−) from 2 months of age for 6 months. Metabolic assessment studies (GTT, ITT, indirect calorimetry) and body composition analysis were performed at the 5th and 6th month of diet-feeding, respectively. At 8 months of age (6 months after diet-feeding), liver, white adipose tissue, and plasma were collected from each mouse for biochemical analysis (n = 7–8 for WT; 5–6 for Mlkl−/− or Mlkl+/−). (B) Body weight of mice represented in grams; percentage of fat mass normalized to total body weight (C) and ratio of lean mass to fat mass in grams (D). (E) Average daily food intake during and light and dark cycles combined. (F) Average daily spontaneous locomotor activity during light and dark phases of the light cycle. White bars/box plots represent CD and gray bars/box plots represent HFHFrHC diet. Error bars are represented as mean ± SEM. One-way ANOVA, * p < 0.05, *** p < 0.0005.