Figure 1.

Dietary sulfur amino acid restriction (SAAR) promotes leanness in liver-specific Atf4-knockdown mice in a sex-dimorphic manner. (A) Graphical overview showing activation of the integrated stress response in response to dietary SAAR and hypothesized eukaryotic initiation factor 2 (eIF2) phosphorylation-independent induction of ATF4. (B) Overview of the genetic mouse models and experimental diets (top) and illustrated timeline of study interventions (bottom). A 1-wk period of control (Ctrl) diet habituation (gray dashed line) was followed by a 10-wk experimental period (black solid line). Mice were placed in a comprehensive laboratory animal monitoring system (CLAMS) for 48 h at the start of week 5. (C) Average cumulative food intake (grams per gram body weight) in male (left) and female (right) mice over the complete 10-wk experimental period. (D) Average change in body weight (g) in male (left) and female (right) mice following the 10-wk experimental period. (E) Average change in fat mass (percentage points) in male (left) and female (right) mice following the 10-wk experimental period. (F) Average change in lean mass (percentage points) in male (left) and female (right) mice following the 10-wk experimental period. (G) Average energy expenditure (kcal/h) measured in the CLAMS: males during light photoperiod (far left), males during dark photoperiod (center left), females during light photoperiod (center right), and females during dark photoperiod (far right). Bar chart values are presented as mean ± SEM with individual data points overlaid. n = 5–12/group. *P < 0.05 with a main effect of diet. n.s. indicates no statistically significant differences at α = 0.05, as determined by two-factor ANOVA and ANCOVA using lean mass as a covariate in the case of energy expenditure.