Fig. 10: Deletion of ATGL in WAT suppresses the effects of G49 in BAT activation and reduces its efficacy in weight loss. | Nature Communications

Fig. 10: Deletion of ATGL in WAT suppresses the effects of G49 in BAT activation and reduces its efficacy in weight loss.

From: The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk

Fig. 10

A BW evolution (ATGLflox/flox, n = 11; ATGLflox/flox + G49, n = 13; ATGLadipoCre, n = 8; ATGLadipoCre + G49, n = 12). Mixed-effect analysis test with Bonferroni post hoc test. p values are detailed in Source data file. B Representative MRI images and total and visceral fat (n = 4 ATGLflox/flox, n = 4 ATGLadipoCre, same mice analyzed before and after 1 week of treatment). Total fat: ATGLflox/flox vs. ATGLflox/flox + G49, ***p < 0.0001; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ###p < 0.0001. Visceral fat: ATGLflox/flox vs. ATGLflox/flox + G49, ***p < 0.0001; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ###p < 0.0001. C Plasma FFAs at 6 h (n = 6 ATGLflox/flox; ATGLflox/flox + G49; ATGLadipoCre; ATGLadipoCre + G49). ATGLflox/flox vs. ATGLflox/flox + G49, ***p < 0.0001; ATGLadipoCre vs. ATGLadipoCre + G49, *p = 0.0102; ATGLflox/flox vs. ATGLadipoCre, $p = 0.0295; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ###p < 0.0001. D MRI analysis of total and visceral fat (n = 4 ATGLflox/flox; ATGLflox/flox + G49; ATGLadipoCre; ATGLadipoCre + G49, each mouse was analyzed before and 6 h post-G40 injection). ΔTotal fat: ATGLflox/flox vs. ATGLflox/flox + G49, ***p < 0.0001; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ###p < 0.0001. ΔVisceral fat: ATGLflox/flox vs. ATGLflox/flox + G49, ***p < 0.0001; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ###p < 0.0001. E Plasma insulin at 6 h (ATGLflox/flox, n = 8; ATGLflox/flox + G49, n = 10; ATGLadipoCre, n = 7; ATGLadipoCre + G49, n = 10). ATGLflox/flox vs. ATGLflox/flox + G49, ***p < 0.0001; ATGLadipoCre vs. ATGLadipoCre + G49, **p = 0.0097; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ###p < 0.0001. F mRNAs in eWAT SVF at 6 h (Il10, ATGLflox/flox, n = 8; ATGLflox/flox + G49, n = 11; ATGLadipoCre, n = 9; ATGLadipoCre + G49, n = 11; Il13, ATGLflox/flox, n = 8; ATGLflox/flox + G49, n = 10; ATGLadipoCre, n = 8; ATGLadipoCre + G49, n = 9; Th, ATGLflox/flox, n = 5; ATGLflox/flox + G49, n = 7; ATGLadipoCre, n = 5; ATGLadipoCre + G49, n = 5). Il10: ATGLflox/flox vs. ATGLflox/flox + G49, ***p < 0.0001; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ###p < 0.0001. Il13: ATGLflox/flox vs. ATGLflox/flox + G49, ***p < 0.0001; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ###p < 0.0001. Th: ATGLflox/flox vs. ATGLflox/flox + G49, *p = 0.0142. G Representative eWAT H&E images at 6 h (Scale bar 250 µm) (n = 4). H Hepatic Cpt1a expression at 72 h (n = 4 in ATGLflox/flox; ATGLflox/flox + G49; ATGLadipoCre; ATGLadipoCre + G49) and FAO (ATGLflox/flox, n = 6; ATGLflox/flox + G49, n = 7; ATGLadipoCre, n = 8; ATGLadipoCre + G49, n = 8). Cpt1a: ATGLflox/flox vs. ATGLflox/flox + G49, *p = 0.0312; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ##p = 0.0090. ASM: ATGLflox/flox vs. ATGLflox/flox + G49, ***p = 0.0003; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ###p = 0.0005. CO2: ATGLflox/flox vs. ATGLflox/flox + G49, **p = 0.0015; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ###p = 0.0002. I Hmcs mRNA (n = 4 in each group), blood ketone bodies (n = 6 in each  group), Fgf21 mRNA (n = 4 in each group) and plasma FGF21 (ATGLflox/flox, n = 5; ATGLflox/flox + G49, n = 6; ATGLadipoCre, n = 5; ATGLadipoCre + G49, n = 6) at 72 h. Hmcs2: ATGLflox/flox vs. ATGLflox/flox + G49, *p = 0.0129; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ##p = 0.0041. Blood ketone bodies: ATGLflox/flox vs. ATGLflox/flox + G49, ***p < 0.0001; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ###p < 0.0001. Fgf21: ATGLflox/flox vs. ATGLflox/flox + G49, ***p < 0.0001; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ###p < 0.0001. Plasma FGF21: ATGLflox/flox vs. ATGLflox/flox + G49, ***p < 0.0001; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ###p = 0.0002. J RER during 3 days of treatment and before and 6 h after first and second injections (n = 4 in ATGLflox/flox and ATGLadipoCre). Light: ATGLflox/flox + G49 vs. ATGLadipoCre + G49: day 1, #p = 0.0236; day 2 and day 3, ###p < 0.0001; ATGLflox/flox + G49: day 0 vs. day 2, ++p = 0.0025; day 0 vs. day 3, ++p = 0.0052. Dark: ATGLflox/flox + G49 vs. ATGLadipoCre + G49: day 1, ##p = 0.0024; day 2, ###p = 0.0009; day 3, ###p < 0.0001. RER (6 h): ATGLflox/flox vs. ATGLadipoCre: 6 h, ###p = 0.0003; t0 h vs. 6 h: ATGLflox/flox, ++p = 0.0048. K Representative BAT H&E images (Scale bar 250 µm) (n = 4), Ucp1 (ATGLflox/flox, n = 4; ATGLflox/flox + G49, n = 6; ATGLadipoCre, n = 4; ATGLadipoCre + G49, n = 6) and representative UCP1 Western blot and quantification (ATGLflox/flox, n = 10; ATGLflox/flox + G49, n = 8; ATGLadipoCre, n = 9; ATGLadipoCre + G49, n = 10). Ucp1: ATGLflox/flox vs. ATGLflox/flox + G49, ***p = 0.0006; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ###p < 0.0001. UCP1 protein levels: ATGLflox/flox vs. ATGLflox/flox + G49, ***p < 0.0001; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ###p < 0.0001. L Representative thermography images and Δ maximal BAT temperature at 1 week (ATGLflox/flox, n = 5; ATGLflox/flox + G49, n = 5; ATGLadipoCre, n = 4; ATGLadipoCre + G49, n = 5). ATGLflox/flox vs. ATGLflox/flox + G49, ***p = 0.0002; ATGLflox/flox + G49 vs. ATGLadipoCre + G49, ###p = 0.0002. M Energy expenditure at 1 week (n = 4). Light: ATGLflox/flox + G49 vs. ATGLadipoCre + G49: day 3, ##p = 0.0024. Dark: ATGLflox/flox + G49 vs. ATGLadipoCre + G49: day 1, #p = 0.0129; day 2, #p = 0.0317; day 3, ###p = 0.0006. ATGLflox/flox + G49: day 0 vs. day 1, +p = 0.0264; day 0 vs. day 2, ++p = 0.0044; day 0 vs. day 3, +++p = 0.0002. B–F, H–M Two-way ANOVA with Bonferroni post hoc test. Data are mean ± SEM. Source data are provided as a Source Data file.

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