Brain-derived neurotrophic factor in the hypothalamic paraventricular nucleus increases energy expenditure by elevating metabolic rate

Abstract

Brain-derived neurotrophic factor (BDNF) decreases food intake and body weight, but few central sites of action have been identified. The hypothalamic paraventricular nucleus (PVN) is important in energy metabolism regulation, and expresses both BDNF and its receptor. We tested three hypotheses: 1) PVN BDNF reduces feeding and increases energy expenditure (EE), 2) PVN BDNF-enhanced thermogenesis results from increased spontaneous physical activity (SPA) and resting metabolic rate (RMR), and 3) PVN BDNF thermogenic effects are mediated, in part, by uncoupling protein 1 (UCP1) in brown adipose tissue (BAT). BDNF (0.5 microg) was injected into the PVN of Sprague-Dawley rats; and oxygen consumption, carbon dioxide production, food intake, and SPA were measured for 24 h in an indirect calorimeter. SPA was also measured in open-field activity chambers for 48 h after BDNF injection. Animals were killed 6 or 24 h after BDNF injection, and BAT UCP1 gene expression was measured with quantitative real-time PCR. BDNF significantly decreased food intake and body weight gain 24 h after injection. Heat production and RMR were significantly elevated for 7 h immediately after BDNF injection. BDNF had no effect on SPA, but increased UCP1 gene expression in BAT at 6 h, but not 24 h after injection. In conclusion, PVN BDNF reduces body weight by decreasing food intake and increasing EE consequent to increased RMR, which may be due, in part, to BAT UCP1 activity. These data suggest that the PVN is an important site of BDNF action to influence energy balance.

Kv1.3 gene-targeted deletion alters longevity and reduces adiposity by increasing locomotion and metabolism in melanocortin-4 receptor-null mice

“…we extend this analysis to other CNS regions, where it is known that insulin and BDNF signaling are involved in energy homeostasis (feeding behaviors, locomotor activity and metabolism), [48][49][50][51][52][53][54][55] it could be plausible that Kv-null animals have increased BDNF sensitivity in areas which normally expresses Kv1.3 13 and would be predicted to demonstrate elevated TrkB in Kv-null mice. More experiments are required to resolve a discrete mechanism that might link loss of Kv1.3 and BDNF activity.…”

“…53,54,58 The PVN has also been shown to be important for mediating BDNF effects on metabolism but not locomotor activity. 52 BDNF's effects on locomotor activity are localized to the forebrain regions as revealed by forebrain-specific knockouts of bdnf 59 and its receptor, trkB.…”

Brain-derived neurotrophic factor in the ventromedial nucleus of the hypothalamus reduces energy intake

“…Low BDNF expression was observed in the hypothalamus of BDNF ϩ/Ϫ heterozygous animals, including the PVN and VMH (36). Bariohay et al (3) reported significant decreases in feeding and body weight gain during chronic infusion of BDNF in the dorsal ventral complex, and our previous work (85,86) indicates that the PVN is an important site of BDNF action.BDNF in the VMH may also play an important role in the regulation of energy metabolism. Both mRNA and protein for BDNF and its receptor TrkB have been identified in the VMH (8,36,87,90).…”

“…Low BDNF expression was observed in the hypothalamus of BDNF ϩ/Ϫ heterozygous animals, including the PVN and VMH (36). Bariohay et al (3) reported significant decreases in feeding and body weight gain during chronic infusion of BDNF in the dorsal ventral complex, and our previous work (85,86) indicates that the PVN is an important site of BDNF action.…”

“…A cannula was deemed correct if the histological examination indicated that the injection was within a 0.25 mm diameter from the targeted site. This rationale is based on diffusion coefficients for the injection volume delivered (57) and work showing effectiveness within this range (85,86). Data from animals with misplaced cannulae were excluded from data analyses.…”