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

Abstract

Recent studies show that brainderived neurotrophic factor (BDNF) decreases feeding and body weight after peripheral and ventricular administration. BDNF mRNA and protein, and its receptor TrkB, are widely distributed in the hypothalamus and other brain regions. However, there are few reports on specific brain sites of actions for BDNF. We evaluated the effect of BDNF, given into the ventromedial nucleus of the hypothalamus (VMH), on normal and deprivation-and neuropeptide Y (NPY)-induced feeding behavior and body weight. BDNF injected unilaterally or bilaterally into the VMH of food-deprived and nondeprived rats significantly decreased feeding and body weight gain within the 0-to 24-h and the 24-to 48-h postinjection intervals. Doses effectively producing inhibition of feeding behavior did not establish a conditioned taste aversion. BDNF-induced feeding inhibition was attenuated by pretreatment of the TrkB-Fc fusion protein that blocks binding between BDNF and its receptor TrkB. VMH-injected BDNF significantly decreased VMH NPY-induced feeding at 1, 2, and 4 h after injection. In summary, BDNF in the VMH significantly decreases food intake and body weight gain, by TrkB receptor-mediated actions. Furthermore, the anorectic effects of BDNF in this site appear to be mediated by NPY. These data suggest that the VMH is an important site of action for BDNF in its effects on energy metabolism. food intake; body weight THE VENTROMEDIAL NUCLEUS OF THE HYPOTHALAMUS (VMH) is a brain area important to the regulation of energy metabolism. Early studies indicated that VMH lesions resulted in hyperphagia and obesity (28,38,66), whereas electrical stimulation of the VMH immediately suppressed feeding and induced lipolysis (65). Glucose-sensing neurons (7,27,55,74,75) and receptors for neuropeptides important to energy metabolism have been identified in the VMH, including leptin (13,17,20,22,51), melanocortin (26), neuropeptide Y (NPY) (43), corticotrophin-releasing hormone (49), CCK (12), insulin (33), and orexin (44) receptors. Many biological agents given into the VMH have been demonstrated to affect feeding. Food intake is inhibited by administration of histamine (4, 47), glucagon-like peptide 1 (70), serotonin agonists (25), urocortin (58), CCK (79), leptin (51), and insulin (78), whereas thyroid hormone (3,5,3Ј-triiodothyronine) (40), GABA or GABA agonists (32,34,35), norepinephrine (73), orexin (74), and NPY induce feeding after administration into the VMH (5,9,24,31,43,56,76).Anatomically, the VMH receives inputs from regions important to the regulation of energy metabolism, including the hypothalamic arcuate nucleus (ARC) (2, 14, 23), lateral hypothalamus (18, 67, 80), amygdala (45, 50), and lateral septum. The VMH also projects to ARC (77), paraventricular nucleus (PVN) (42, 52), lateral hypothalamus (72, 80), dorsomedial nucleus of the hypothalamus (46, 80), amygdala (6, 68), lateral septum (68), ventral tegmental area (68), nucleus accumbens (6), and nucleus of the solitary tract (6). These behavioral and neuroanatom...

Selective Deletion ofBdnfin the Ventromedial and Dorsomedial Hypothalamus of Adult Mice Results in Hyperphagic Behavior and Obesity

“…This suggests that VMH-derived BDNF might exert its satiety effects by acting locally within this nucleus in an autocrine or paracrine manner. In support of this, it was reported recently that BDNF infusion into the VMH triggered reductions in food consumption and body weight (Wang et al, 2007c). BDNF produced in the VMH could also interact with several intrahypothalamic or extrahypothalamic regions to signal for satiety, including the DMH, Arc, PVN, amygdala, nucleus accumbens, and nucleus of the solitary tract (Canteras et al, 1994).…”

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.…”

“…The effects of BDNF on feeding but not locomotor activity, have been shown to be mediated by the ventromedial, dorsomedial and paraventricular nuclei (PVN) of the hypothalamus. 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.…”

Protein-tyrosine Phosphatase 1B (PTP1B) Is a Novel Regulator of Central Brain-derived Neurotrophic Factor and Tropomyosin Receptor Kinase B (TrkB) Signaling

“…The hypothalamus and the hindbrain are two major regions within the brain that are implicated in BDNF regulation of metabolism, although both BDNF and the TrkB receptor are broadly distributed throughout the central nervous system (21,22). Intraparenchymal administration of BDNF into the ventromedial nucleus and paraventricular nucleus of the hypothalamus reduces food intake and increases energy expenditure (23)(24)(25)(26)(27)(28). Similarly, delivery of BDNF directly into the dorsal vagal complex (29,30) or nucleus tractus solitarius (31) of the hindbrain reduces food intake and increases energy expenditure.…”