Endo1 silencing in the ARC of mice prior to DIO prevents obesity but impairs glucose homeostasis on HFD. (A) Experimental Protocol for the “Obesity prevention experiment”. (B) Body weight after stereotactic injection of lentiviral vectors expressing control (CTRL) or Endo1 shRNA in the ARC and kept on CD (CTRL or Endo1-CD-CD) or switched to HFD (CTRL or Endo1-CD-HFD). CTRL-CD-HFD vs Endo1-CD-HFD: *, p < 0.05; **, p < 0.01; ***, p < 0.005; ****, p < 0.001. (n = 8 per group). (C) Intraperitoneal Glucose Tolerance Test (ip-GTT) (2 g/kg). CTRL-CD-HFD vs Endo1-CD-HFD: *, p < 0.05 (n = 15–18 per group). (D) Area Under the Curve (AUC) of (C). ****, p < 0.001. (E) Intraperitoneal Glucose Tolerance Test (ip-GTT) normalized to fasting blood glucose of HFD mice. *, p < 0.05; ***, p < 0.005 (n = 15–18 per group). (F) Oral Glucose Tolerance Test (o-GTT) (3 g/kg) (n = 8 per group). (G) Oral Glucose Tolerance Test (o-GTT) normalized to fasting blood glucose of HFD mice. *, p < 0.05; **, p < 0.01 (n = 8 per group). (H) Glucose utilization rate, endogenous glucose production (EndoRa), and glucose infusion rate required to maintain euglycemia in euglycemic hyperinsulinemic clamp. *, p < 0.05 (n = 4 per group). Data are presented as means ± SEM.