p38α blocks brown adipose tissue thermogenesis through p38δ inhibition
Fig 2
p38αFab-KO mice are protected against diet-induced obesity and diabetes.
(A) Body weight time course in Fab-Cre and p38αFab-KO male (8–10-wk-old) mice fed an HFD over 8 weeks. Data are presented as the increase above initial weight (left panel) or as total weight comparing mice fed an HDF with mice fed an ND (right panel). HFD-induced weight gain was significantly higher in Fab-Cre than p38αFab-KO mice (mean ± SEM; Fab-Cre HFD n = 10 mice; p38αFab-KO HFD n = 11 mice; Fab-Cre ND n = 9 mice; p38αFab-KO ND n = 8 mice). (B) NMR analysis of fat mass in p38αFab-KO and Fab-Cre mice after 8 weeks of HFD (mean ± SEM; Fab-Cre n = 10 mice; p38αFab-KO n = 8 mice). (C) Representative haematoxylin–eosin and oil red O staining of liver sections (Fab-Cre n = 6 mice; p38αFab-KO n = 6 mice; and 3 pictures from each mouse). Scale bar: 50 μm. (D) Fasting and fed blood glucose in Fab-Cre and p38αFab-KO mice fed the HFD (8 weeks) (mean ± SEM; Fab-Cre n = 10 mice; p38αFab-KO n = 11 mice). (E) GTT and ITT in Fab-Cre and p38αFab-KO mice fed the HFD for 8 weeks. Mice were fasted overnight (for GTT) or 1 hour (for ITT), and blood glucose concentration was measured in mice given intraperitoneal injections of glucose (1 g/kg of total body weight) or insulin (0.75 U/kg of total body weight) (mean ± SEM; Fab-Cre n = 10 mice; p38αFab-KO n = 11 mice). (F) Immunohistochemistry of eWAT sections using anti-GLUT4 (green), anti-Cav-1 (red) antibodies, and the nuclear dye DAPI (blue). Location of GLUT4 was analysed in mice treated without or with insulin (1.5 IU/kg) for 15 minutes after overnight fasting. Scale bar: 20 μm. (G) Representative haematoxylin–eosin BAT and eWAT sections (Fab-Cre n = 6 mice; p38αFab-KO n = 6 mice; and 3 pictures from each mouse). Scale bar: 50 μm. *p < 0.05, ***p < 0.001 Fab-Cre versus p38αFab-KO. ‘&&’ indicates p < 0.01, ‘&&&’ indicates p < 0.001 Fab-Cre ND versus Fab-Cre HFD (2-way ANOVA coupled with Bonferroni’s post-tests or t test or Welch’s test when variances were different). See also S1 Data. BAT, brown adipose tissue; Cav-1, caveolin-1; eWAT, epididymal fat; GLUT4, glucose transporter type 4; GTT, glucose tolerance test; HFD, high-fat diet; ITT, insulin tolerance test; ND, normal-chow diet; WAT, white adipose tissue.