FIG. 1. Time line illustrating the course of treatments and tests for experiment 2. icv, intracerebroventricular. FIG. 1. Time line illustrating the course of treatments and tests for experiment 2. icv, intracerebroventricular. More

FIG. 4. Intraperitoneal and intracerebroventricular leptin are sufficient to alter body composition and serum insulin levels. Adipose tissue and gastrocnemius muscle weights in mice treated with intraperitoneal (A, C) or intracerebroventricular (B, D) leptin for 1 week are shown. GTTs (E, F) and serum insulin levels (G, H) before and 30 min after glucose injection are shown. Numbers of animals are indicated in each figure. For intraperitoneal leptin study, ^aP < 0.05 vs. wt RF; ^bP < 0.05 vs. ob/ob RF; ^cP < 0.05 vs. ob/ob CR. For intracerebroventricular leptin study, ^aP < 0.05 vs. wt CR intracerebroventricular saline; ^cP < 0.05 vs. ob/ob CR intracerebroventricular saline. icv, intracerebroventricular; L 1 wk, 1 week of leptin treatment; RF, random fed; wt, wild type. FIG. 4. Intraperitoneal and intracerebroventricular leptin are sufficient to alter body composition and serum insulin levels. Adipose tissue and gastrocnemius muscle weights in mice treated with intraperitoneal (A, C) or intracerebroventricular (B, D) leptin for 1 week are shown. GTTs (E, F) and serum insulin levels (G, H) before and 30 min after glucose injection are shown. Numbers of animals are indicated in each figure. For intraperitoneal leptin study, aP < 0.05 vs. wt RF; bP < 0.05 vs. ob/ob RF; cP < 0.05 vs. ob/ob CR. For intracerebroventricular leptin study, aP < 0.05 vs. wt CR intracerebroventricular saline; cP < 0.05 vs. ob/ob CR intracerebroventricular saline. icv, intracerebroventricular; L 1 wk, 1 week of leptin treatment; RF, random fed; wt, wild type. More

FIG. 1. Central administration of apoE dose-dependently reduced food intake at the beginning of the dark period in ad libitum–fed (A) or 24 h–fasted (B) rats. Values are expressed as means ± SE, n = 7. icv, intracerebroventricular. *P < 0.05, **P < 0.01 vs. saline controls. FIG. 1. Central administration of apoE dose-dependently reduced food intake at the beginning of the dark period in ad libitum–fed (A) or 24 h–fasted (B) rats. Values are expressed as means ± SE, n = 7. icv, intracerebroventricular. *P < 0.05, **P < 0.01 vs. saline controls. More

Figure 1 Effect of central leptin infusion on glucose levels in T1D LIC:Vgat^flox/flox and LIC:Vglut2^flox/flox mice. A: Representative images of pancreata from non-T1D and T1D mice costained for insulin (red) and glucagon (green). Scale bars = 25 μm. Measurements for plasma glucose levels (B) and daily food intake (C). All data are presented as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. other groups (n = 5–8). icv, intracerebroventricular. Figure 1. Effect of central leptin infusion on glucose levels in T1D LIC:Vgatflox/flox and LIC:Vglut2flox/flox mice. A: Representative images of pancreata from non-T1D and T1D mice costained for insulin (red) and glucagon (green). Scale bars = 25 μm. Measurements for plasma glucose levels (B) and daily food intake (C). All data are presented as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. other groups (n = 5–8). icv, intracerebroventricular. More

FIG. 5. Intraperitoneal and intracerebroventricular leptin are sufficient to normalize basal and insulin-stimulated palmitate oxidation in caloric-restricted ob/ob hearts. Basal and insulin-stimulated palmitate oxidation after 1 week of intraperitoneal (A) or intracerebroventricular leptin (B). C and D: qPCR analysis from noninsulin-stimulated perfused hearts. WT RF values are normalized to 1 and shown as the dashed line. MCAD, medium chain acyl CoA dehydrogenase; LCAD, long chain acyl CoA dehydrogenase; CD36, CD36 antigen; HADHa, hydroxyacyl-CoA dehydrogenase α-subunit; HADHb, hydroxyacyl-CoA dehydrogenase β-subunit. For intraperitoneal leptin study, ^aP < 0.05 vs. wt RF; ^bP < 0.05 vs. ob/ob RF; ^cP < 0.05 vs. ob/ob CR; *P < 0.05 vs. noninsulin-stimulated hearts from the same treatment group. For intracerebroventricular leptin study, ^aP < 0.05 vs. wt CR intracerebroventricular saline; ^cP < 0.05 vs. ob/ob CR intracerebroventricular saline; *P < 0.05 vs. noninsulin-stimulated hearts from the same treatment group. CR, caloric restriction; dhw, dry heart weight; icv, intracerebroventricular; L 1 wk, 1 week of leptin treatment; RF, random fed; wt, wild type. FIG. 5. Intraperitoneal and intracerebroventricular leptin are sufficient to normalize basal and insulin-stimulated palmitate oxidation in caloric-restricted ob/ob hearts. Basal and insulin-stimulated palmitate oxidation after 1 week of intraperitoneal (A) or intracerebroventricular leptin (B). C and D: qPCR analysis from noninsulin-stimulated perfused hearts. WT RF values are normalized to 1 and shown as the dashed line. MCAD, medium chain acyl CoA dehydrogenase; LCAD, long chain acyl CoA dehydrogenase; CD36, CD36 antigen; HADHa, hydroxyacyl-CoA dehydrogenase α-subunit; HADHb, hydroxyacyl-CoA dehydrogenase β-subunit. For intraperitoneal leptin study, aP < 0.05 vs. wt RF; bP < 0.05 vs. ob/ob RF; cP < 0.05 vs. ob/ob CR; *P < 0.05 vs. noninsulin-stimulated hearts from the same treatment group. For intracerebroventricular leptin study, aP < 0.05 vs. wt CR intracerebroventricular saline; cP < 0.05 vs. ob/ob CR intracerebroventricular saline; *P < 0.05 vs. noninsulin-stimulated hearts from the same treatment group. CR, caloric restriction; dhw, dry heart weight; icv, intracerebroventricular; L 1 wk, 1 week of leptin treatment; RF, random fed; wt, wild type. More

Figure 5 Disruption of the LepR → STAT3 signaling pathway abrogated the antidiabetic effect of central leptin. A: Plasma glucose levels (n = 4–7). ***P < 0.001 vs. the other groups. B: Daily food intake (n = 4–7). **P < 0.01 vs. the other groups. C: Representative images of pancreata from saline- and leptin-treated T1D LepRs/s mice costained for insulin (red) and glucagon (green). Scale bars = 25 μm. D: Plasma insulin levels were measured at day 13 (n = 4–6). ***P < 0.001 vs. all other groups. E: Expression of p-S6 by intraperitoneal (i.p.) leptin treatment in the hypothalamus of the indicated mouse groups. Scale bars = 250 μm. 3V, third ventricle. Levels of plasma glucagon (F) and corticosterone (G) were measured at day 13. *P < 0.05 vs. the other groups. All data are represented as the mean ± SEM. icv, intracerebroventricular. Figure 5. Disruption of the LepR → STAT3 signaling pathway abrogated the antidiabetic effect of central leptin. A: Plasma glucose levels (n = 4–7). ***P < 0.001 vs. the other groups. B: Daily food intake (n = 4–7). **P < 0.01 vs. the other groups. C: Representative images of pancreata from saline- and leptin-treated T1D LepRs/s mice costained for insulin (red) and glucagon (green). Scale bars = 25 μm. D: Plasma insulin levels were measured at day 13 (n = 4–6). ***P < 0.001 vs. all other groups. E: Expression of p-S6 by intraperitoneal (i.p.) leptin treatment in the hypothalamus of the indicated mouse groups. Scale bars = 250 μm. 3V, third ventricle. Levels of plasma glucagon (F) and corticosterone (G) were measured at day 13. *P < 0.05 vs. the other groups. All data are represented as the mean ± SEM. icv, intracerebroventricular. More

Figure 4 Effects of central leptin infusion in LIC:Vgat^flox/flox:Vglut2^flox/flox mice with T1D. A: Representative images of pancreata from non-T1D and T1D mice costained for insulin (red) and glucagon (green). Scale bars = 25 μm. B: Expression of pSTAT3 in the hypothalamus taken from LIC:Vgat^flox/flox:Vglut2 ^flox/flox mice at day 13 of the experiment. Scale bar = 250 μm. f, fornix. C: Plasma glucose levels (n = 4–6). ***P < 0.001 vs. the other groups, #P < 0.05 vs. control/T1D/leptin group. D: Daily food intake (n = 5–6). *P < 0.05, **P < 0.01, #P < 0.05, ##P < 0.01 vs. control/T1D/saline group. E: Plasma insulin levels were measured at day 13 (n = 5). ***P < 0.001 vs. the other groups. Plasma glucagon (F) and corticosterone (G) levels were measured at day 13 (n = 5–6). *P < 0.05, **P < 0.01 vs. the other groups. All data are represented as the mean ± SEM. icv, intracerebroventricular. Figure 4. Effects of central leptin infusion in LIC:Vgatflox/flox:Vglut2flox/flox mice with T1D. A: Representative images of pancreata from non-T1D and T1D mice costained for insulin (red) and glucagon (green). Scale bars = 25 μm. B: Expression of pSTAT3 in the hypothalamus taken from LIC:Vgatflox/flox:Vglut2 flox/flox mice at day 13 of the experiment. Scale bar = 250 μm. f, fornix. C: Plasma glucose levels (n = 4–6). ***P < 0.001 vs. the other groups, #P < 0.05 vs. control/T1D/leptin group. D: Daily food intake (n = 5–6). *P < 0.05, **P < 0.01, #P < 0.05, ##P < 0.01 vs. control/T1D/saline group. E: Plasma insulin levels were measured at day 13 (n = 5). ***P < 0.001 vs. the other groups. Plasma glucagon (F) and corticosterone (G) levels were measured at day 13 (n = 5–6). *P < 0.05, **P < 0.01 vs. the other groups. All data are represented as the mean ± SEM. icv, intracerebroventricular. More

FIG. 7. A brain ROS donor increases femoral arterial blood flow and reduces heart rate in a dose-dependent manner. In A, the femoral arterial blood flow rate was recorded under basal conditions. aCSF or hydrogen peroxide (H₂O₂, low 2 nmol/min and high 20 nmol/min) were infused in the lateral ventricle at the time indicated by the arrow. Statistical significance (P < 0.05) was determined between mice infused with aCSF or H₂O₂. In B, the femoral arterial blood flow rate was recorded in hyperglycemic conditions and in the presence of Ex4 infused into the brain (arrow at −30 min). After 120 min, an infusion of hydrogen peroxide was performed in a separate group of mice (see arrow at 120 min, 20 nmol/min). aCSF infusion under the same experimental conditions did not modify the blood flow (not shown). In C, the mean heart rate was recorded simultaneously. Data are means ± SE for 5–7 mice per group. icv, intracerebroventricular; iv, intravenous. FIG. 7. A brain ROS donor increases femoral arterial blood flow and reduces heart rate in a dose-dependent manner. In A, the femoral arterial blood flow rate was recorded under basal conditions. aCSF or hydrogen peroxide (H2O2, low 2 nmol/min and high 20 nmol/min) were infused in the lateral ventricle at the time indicated by the arrow. Statistical significance (P < 0.05) was determined between mice infused with aCSF or H2O2. In B, the femoral arterial blood flow rate was recorded in hyperglycemic conditions and in the presence of Ex4 infused into the brain (arrow at −30 min). After 120 min, an infusion of hydrogen peroxide was performed in a separate group of mice (see arrow at 120 min, 20 nmol/min). aCSF infusion under the same experimental conditions did not modify the blood flow (not shown). In C, the mean heart rate was recorded simultaneously. Data are means ± SE for 5–7 mice per group. icv, intracerebroventricular; iv, intravenous. More

FIG. 4. Hypothalamic ROS production is required to restrain food intake during hypertriglyceridemia. A: Experimental procedures of food intake measurement. B: Effect of GSH-EE cerebral delivery on hypertriglyceridemia-induced ROS production. GSH-EE or vehicles were infused in the third lateral ventricle before intraperitoneal injection of either intralipid (IL) or saline. ROS levels were assessed in ventral hypothalamus 30 min after intraperitoneal injection as described above. Data are means ± SE (n = 6). *Significant differences between vehicle and controls, P < 0.05. ‡Significant differences between vehicle- and intralipid-treated rats, P < 0.05. C: Effect of GSH-EE cerebral delivery on the hypertriglyceridemia-induced satiety. Food intake was assessed by weighing residual chow at different times. Data are means ± SE (n = 6). *Significant differences between vehicle and controls, P < 0.05. ‡Significant differences between vehicle- and intralipid-treated rats, P < 0.05. icv, intracerebroventricular; IL, intralipid. FIG. 4. Hypothalamic ROS production is required to restrain food intake during hypertriglyceridemia. A: Experimental procedures of food intake measurement. B: Effect of GSH-EE cerebral delivery on hypertriglyceridemia-induced ROS production. GSH-EE or vehicles were infused in the third lateral ventricle before intraperitoneal injection of either intralipid (IL) or saline. ROS levels were assessed in ventral hypothalamus 30 min after intraperitoneal injection as described above. Data are means ± SE (n = 6). *Significant differences between vehicle and controls, P < 0.05. ‡Significant differences between vehicle- and intralipid-treated rats, P < 0.05. C: Effect of GSH-EE cerebral delivery on the hypertriglyceridemia-induced satiety. Food intake was assessed by weighing residual chow at different times. Data are means ± SE (n = 6). *Significant differences between vehicle and controls, P < 0.05. ‡Significant differences between vehicle- and intralipid-treated rats, P < 0.05. icv, intracerebroventricular; IL, intralipid. More