Fig. 5.

Acute reversal of obesity-related disorders by inhibiting brain ER stress. Male C57BL/6 mice were maintained on normal chow (Chw) or HFD for 5 mo, since 2 mo of age, and then implanted with third-ventricle cannula. After 2 wk of postoperative recovery, mice received third-ventricle injection of 1.0 μg of TUDCA (TU) or vehicle (Veh) on the night of day 1, followed by overnight fasting and a second injection of TUDCA or vehicle in the morning of day 2. (A–E) Mice at 2 h postinjection on day 2 were separately subjected to GTT (A and B), ITT (C and D), and plasma insulin measurement (E). AUC data of GTT (B) and ITT (D) are presented. ITT data are presented as the percentages of time-course blood glucose over the baseline levels (C) and the percentages of AUC values of treatment groups over the control group (D). *P < 0.05; **P < 0.01; n = 8–9 mice per group. (F and G) Mice at 2 h postinjection on day 2 were anesthetized and challenged with insulin (INS; 5.0 units/kg) or saline for 3 min via abdominal aorta injection. Liver samples were rapidly harvested and analyzed for insulin signaling with immunoprecipitation (IP) and Western blotting. (G) Phosphorylated IRβ (p-IRβ), phosphorylated IRS2 (p-IRS2), binding of p85 to IRS2, and phosphorylated Akt (p-Akt) were quantitatively normalized by the total protein levels (Total) of IRβ, IRS2, p85, and Akt, respectively. β-actin (β-act) was used as an internal control. **P < 0.01; n = 4–6 mice per group; AU, arbitrary unit. (H) Liver tissues were harvested from chow-fed versus HFD-fed mice after 2-d TUDCA or vehicle treatment and analyzed for mRNA levels of pepck and g6pase. *P < 0.05; n = 4–6 mice per group; AU, arbitrary unit. (I–K) Mice were continuously monitored for BP and heart rates (HR) via preimplanted artery BP telemetric probes. Data presented represent average BP values over a 2-h period after TUDCA or vehicle injection on day 2. SBP, systolic BP; DBP, diastolic BP; MBP, mean BP. *P < 0.05; **P < 0.01; n = 4 mice per group. (Error bars reflect mean ± SEM.)