Fig. 5: Pharmacological inhibition of 11β-HSD1 in osteoblasts attenuates the established high-fat diet-induced obesity, and related glucose handling impairment and bone loss.
From: Targeting osteoblastic 11β-HSD1 to combat high-fat diet-induced bone loss and obesity
a Design of the bone-targeted 11β-HSD1 inhibitor, (DSS)6-AZD8329. b, c Organ distribution and skeletal distribution of (DSS)6-AZD8329 (n = 3) and (RKK)6-AZD8329 (n = 3). b The organ distribution. c The skeletal distribution, scale bar=20 μm. d Experimental design of wild-type mice treated with (DSS)6-AZD8329 and (RKK)6-AZD8329. e–g The micro-CT analysis and bone histometric analysis. e The trabecular bone and cortical bone microstructure. f The percentage change of trabecular bone volume/total volume (Tb. BV/TV) and trabecular bone density (Tb. v. BMD). g The percentage change of cortical bone density (Ct. v. BMD). h The calcein double labeling, scale bar=20 μm. i The percentage change of mineral apposition rate (MAR), bone formation rate per bone surface (BFR/BS) and the number of osteoblasts per bone surface (N.Ob/BS). j–k Weight gain and energy intake during HFD. *P < 0.05, **P < 0.01, ***P < 0.001 when other groups vs. HFD+vehicle group. j Weight gain. k Energy intake. l Weights and representative photographs of gonadal white adipose tissues (gWAT). m–o Glucose handling tests (n = 8 for two vehicle-treated groups, n = 12 for two drug-treated groups). *P < 0.05, **P < 0.01, ***P < 0.001 when other groups vs. HFD + vehicle group. m Fasting blood glucose. n: Insulin tolerance test (ITT). o Oral glucose tolerance test (oGTT). p Glucose uptake tests (n = 8 for two vehicle-treated groups, n = 12 for two drug-treated groups). Left: Representative images of glucose uptake. Right: Quantitative analysis of glucose uptake into liver, WAT, muscle and bone. q Skeletal mRNA expression of Hsd11b1, Gilz, Egr2, Pik3cb and Glut4. Note: Data were presented as mean value ± SEM for (f, g, i–q). Chow+vehicle (n = 8), mice with Chow feeding and start administration of vehicle since week 8; HFD+vehicle (n = 8), HFD + (RKK)6-AZD8329 (n = 13), HFD + (DSS)6-AZD8329 (n = 13), mice with HFD feeding and start administration of vehicle, (RKK)6-AZD8329, or (DSS)6-AZD8329, respectively, since week 8. All samples are biologically independent samples. Statistical significance was calculated using one-way ANOVA followed by Tukey’s post-hoc test (f–g, i, l, m–q) and two-way ANOVA followed by Sidak’s multiple comparisons test (j–k, n–o). All tests were two-sided.
