Figure 6. Genetic hyperleptinemia causes auranofin resistance.

Tamoxifen treatment induced LepR deletion and obesity in Ubc-Cre;LepR^lp/lp (LepR KO) mice. After four weeks, LepR KO mice were i.p. injected with auranofin (1 mg/kg) or vehicle for 4 weeks (n=5/group). (A) Body mass during treatments. (B) Body composition and (C) tissue weights at necropsy (n=5/group). (D) eWAT Lep in wild-type mice treated with auranofin on high fat diet (WT+HFD; n=4/group) and LepR KO (n=5/group). (E) Fed serum leptin and corresponding leptin to adiponectin ratio (n=10/group). Mice were individually housed in CLAMS cages for 6 days (n=5/group). Averaged data during dark/light periods for (F) food intake, (G) RER, (H) locomotor activity and wheel running. (I) ITT and (J) GTT with corresponding area under the curve measurements. (K) Fasting serum insulin (n=5/group). (L) Oil Red O (ORO) staining of liver sections (scale=100 μm) and liver triglycerides (TGs) (n=6/group). (M) eWAT H&E; scale=50 μm. (N) Expression of inflammatory, fibrosis and metabolism genes in eWAT (n=5/group). (O) Reverse phase protein array on eWAT of LepR KO mice shown as log₂ fold change auranofin/vehicle.

All data are mean ± SEM. *p<0.05, #p<0.1 by two-way ANOVA with Tukey’s multiple comparison test (A; B; D; G, day/night food intake; I; J), ANCOVA with lean mass as a co-variate (G; H), and unpaired t-test (C; E; F, cumulative food intake; I and J, AUC; L; N; O)