Brain-derived neurotrophic factor (BDNF) in the hypothalamic ventromedial nucleus increases energy expenditure

Abstract

Brain-derived neurotrophic factor (BDNF) decreases food intake and body weight, but few central sites of action have been identified for its effect on energy expenditure. The hypothalamic ventromedial nucleus (VMH) is important in regulating energy metabolism. Our previous work indicated that BDNF in the VMH reduced food intake. The purposes of the study were to determine: 1) if BDNF in the VMH increases energy expenditure (EE); 2) if BDNF-enhanced thermogenesis results from increased spontaneous physical activity (SPA) and resting metabolic rate (RMR); and 3) if VMH BDNF thermogenic effects are mediated by uncoupling protein 1 (UCP1) in brown adipose tissue (BAT). BDNF (0.5 microg) was injected into the VMH of male Sprague-Dawley rats and oxygen consumption, carbon dioxide production, food intake and SPA were measured for 24h in an indirect calorimeter. Animals were sacrificed 4h after BDNF injection, and BAT UCP1 gene expression was measured with quantitative real-time polymerase chain reaction. BDNF significantly decreased food and water intake, and body weight gain. Heat production and RMR were significantly elevated for 9h immediately after BDNF injection. BDNF increased SPA and EE during SPA (aEE) within 9h after injection although BDNF had no effect on 0-24h SPA and aEE. BDNF did not induce a significant increase in BAT UCP1 expression. In conclusion, VMH BDNF reduces body weight by decreasing food intake and increasing EE consequent to increased SPA and RMR, suggesting that the VMH is an important site of BDNF action to influence energy balance.

Fig. 1

Effect of BDNF in the VMH on food intake (A), water intake (B) and body weight gain (C) during the 24 h post-injection period. * P < 0.05; # P < 0.01; n = 17.

Fig. 2

Time course of total energy expenditure (EE) calorimetric index after BDNF injection into the VMH. Total EE in 0–9 h, dark phase and 0–24 h post-injection period is shown in the inset. Since the measurement among rats started between 10:00 AM and 12:00 PM, the period lengths between injection and the beginning of the dark phase (7:00 PM) were variable. The horizontal bar above the x-axis represents the time spent in the dark phase after injection. The central dark bar plus the right or left short gray bar indicates 12 h spent in the dark phase and represents animals injected between 10 AM (the right gray bar plus the dark bar) and 12 PM (the left gray bar plus the dark bar), respectively. * P < 0.05; n = 17.

Fig. 3

Time course of total SPA after administration of BDNF in the VMH. The SPA (total number of beam breaks caused by natural motion in the cage) in the 0 – 9 h, dark phase, and 0–24 h post-injection intervals are shown in the inset. Since the measurement among rats started between 10:00 AM and 12:00 PM, the period lengths between injection and the beginning of the dark phase (7:00 PM) were variable. The horizontal bar above the x-axis represents the time spent in the dark phase after injection. The central dark bar plus the right or left short gray bar indicates 12 h spent in the dark phase and represents animals injected between 10 AM (the right gray bar plus the dark bar) and 12 PM (the left gray bar plus the dark bar), respectively.* P < 0.05;; n = 17.

Fig. 4

Association between hourly total energy expenditure (EE) and hourly SPA after administration of aCSF (A) or BDNF (B). Each dot represents the average value during each one hour time period. n = 17.

Fig. 5

Time course of time spent on SPA after administration of BDNF in the VMH. The time spent on SPA in the 0 – 9 h, dark phase, and 0–24 h post-injection intervals are shown in the inset. Since the measurement among rats started between 10:00 AM and 12:00 PM, the period lengths between injection and the beginning of the dark phase (7:00 PM) were variable. The horizontal bar above the x-axis represents the time spent in the dark phase after injection. The central dark bar plus the right or left short gray bar indicates 12 h spent in the dark phase and represents animals injected between 10 AM (the right gray bar plus the dark bar) and 12 PM (the left gray bar plus the dark bar), respectively.* P < 0.05; n = 17.

Fig. 6

Time course of hourly energy expenditure during physical activity (aEE) after administration of BDNF in the VMH. The aEE in the 0 – 9 h, dark phase, and 0–24 h post-injection intervals are shown in the inset. Since the measurement among rats started between 10:00 AM and 12:00 PM, the period lengths between injection and the beginning of the dark phase (7:00 PM) were variable. The horizontal bar above the x-axis represents the time spent in the dark phase after injection. The central dark bar plus the right or left short gray bar indicates 12 h spent in the dark phase and represents animals injected between 10 AM (the right gray bar plus the dark bar) and 12 PM (the left gray bar plus the dark bar), respectively.* P < 0.05; n = 17.

Fig. 7

Time course of hourly energy expenditure during resting (rEE) after administration of BDNF in the VMH. rEE in the 0 – 7 h, dark phase, and 0–24 h post-injection intervals are shown in the inset. Since the measurement among rats started between 10:00 AM and 12:00 PM, the period lengths between injection and the beginning of the dark phase (7:00 PM) were variable. The horizontal bar above the x-axis represents the time spent in the dark phase after injection. The central dark bar plus the right or left short gray bar indicates 12 h spent in the dark phase and represents animals injected between 10 AM (the right gray bar plus the dark bar) and 12 PM (the left gray bar plus the dark bar), respectively.* P < 0.05; n = 17.

Fig. 8

Time course of the hourly mean resting metabolic rate (hRMR) after administration of BDNF in the VMH. The mean 24-h resting metabolic rate (mRMR) is shown in the inset. Since the measurement among rats started between 10:00 AM and 12:00 PM, the period lengths between injection and the beginning of the dark phase (7:00 PM) were variable. The horizontal bar above the x-axis represents the time spent in the dark phase after injection. The central dark bar plus the right or left short gray bar indicates 12 h spent in the dark phase and represents animals injected between 10 AM (the right gray bar plus the dark bar) and 12 PM (the left gray bar plus the dark bar), respectively.* P < 0.05; n = 17.

Fig. 9

Time course of the hourly mean respiratory exchange ratio (RER) after administration of BDNF in the VMH. The mean 24-h RER is shown in the inset. Since the measurement among rats started between 10:00 AM and 12:00 PM, the period lengths between injection and the beginning of the dark phase (7:00 PM) were variable. The horizontal bar above the x-axis represents the time spent in the dark phase after injection. The central dark bar plus the right or left short gray bar indicates 12 h spent in the dark phase and represents animals injected between 10 AM (the right gray bar plus the dark bar) and 12 PM (the left gray bar plus the dark bar), respectively.* P < 0.05; n = 17.