Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor

Abstract

The melanocortin-4 receptor (MC4R) is critically involved in regulating energy balance, and obesity has been observed in mice with mutations in the gene for brain-derived neurotrophic factor (BDNF). Here we report that BDNF is expressed at high levels in the ventromedial hypothalamus (VMH) where its expression is regulated by nutritional state and by MC4R signaling. In addition, similar to MC4R mutants, mouse mutants that expresses the BDNF receptor TrkB at a quarter of the normal amount showed hyperphagia and excessive weight gain on higher-fat diets. Furthermore, BDNF infusion into the brain suppressed the hyperphagia and excessive weight gain observed on higherfat diets in mice with deficient MC4R signaling. These results show that MC4R signaling controls BDNF expression in the VMH and support the hypothesis that BDNF is an important effector through which MC4R signaling controls energy balance.Neurotrophins are a family of structurally related growth factors, including brain-derived neurotrophic factor (BDNF), that exert many of their effects on neurons through Trk receptor tyrosine kinases. Among these, BDNF and its receptor TrkB are the most widely and abundantly expressed in the brain. BDNF has been shown to regulate neuronal development and to modulate synaptic plasticity 1 . Obesity phenotypes have been observed in BDNF heterozygous mice and in mice in which the BDNF gene has been deleted in excitatory neurons in the brain 2-4 . These mutants also show hyperactivity, hyperleptinaemia, hyperinsulinaemia, hyperglycemia and increased linear growth 3,4 . Moreover, both central and peripheral administration of BDNF decrease food intake, increase energy expenditure and ameliorate hyperinsulinaemia and hyperglycemia in diabetic db/db mice 5-8 . However, the means by which BDNF alters energy balance and the relationship of TrkB signaling to the major pathways previously shown to be involved in the regulation of energy balance remain unknown. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. The status of energy balance is communicated to the hypothalamus through neuronal and hormonal signals. Several hypothalamic nuclei are involved in the regulation of energy balance, including the ventromedial (VMH), paraventricular (PVN) and arcuate (ARC) hypothalamic nuclei and the lateral hypothalamic area (LH). Although the observation that bilateral VMH lesions produce hyperphagia and obesity has implicated this region in the regulation of energy balance 9-11 , the neural mechanisms through which the VMH functions to influence energy balance are not clear. NIH Public AccessOne of the major signals that serves as a monitor of energy balance is leptin, a polypeptide generated in adipocytes 12 . One of the main targets of leptin in the hypothalamus is the ARC, a region containing at least two distinct populations of neurons 13-15 . One population of neurons expresses two orexigenic polypeptides, neuropeptide Y (NPY) and agouti-related protein (AgRP), whereas the other...

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

“…Role m In satiety; m water reward (Horger et al, 1999;Kernie et al, 2000;Nakagawa et al, 2003); improvement in glucose metabolism (Tonra et al, 1999;Nakagawa et al, 2000;Ono et al, 2000) m Drug reward (Horger et al, 1999) K BDNF in mesolimbic pathways regulates appetitive behavior (Eisch et al, 2003;Itoh et al, 2004); BDNF within hypothalamus regulates energy balance by enhancing catabolic processes (Xu et al, 2003) K BDNF may play a role in behavioral sensitization to drugs (Guillin et al, 2001) and potentially to palatable food via its dopaminergic and opioidergic (Siuciak et al, 1994;Siuciak et al, 1995) effects Repeated exposure kIn the hippocampus (Molteni et al, 2002;Molteni et al, 2004) m In mesocorticolimbic areas including, hypothalamus (Meredith et al, 2002;Butovsky et al, 2005); m and upregulation of BDNF receptors during withdrawal (Toda et al, 2002;Grimm et al, 2003); incubation of drug craving, accompanied by m in BDNF (Grimm et al, 2003) BDNF gene knockout animals m In food intake and obesity (Lyons et al, 1999;Kernie et al, 2000;Rios et al, 2001;Xu et al, 2003) k Drug reward (Hall et al, 2003;Horger et al, 1999) Orexin m Food intake (Edwards et al, 1999;Harris et al, 2005) Relapse to drug seeking behavior (Harris et al, 2005) Activated by SGAs ( Ibanez-Rojo et al, 1993;Bencherif et al, 2005) are available, though, to extend preclinical palatable food opioid findings to humans. Neuroimaging studies in obese people reported in...…”

“…In mesolimbic dopaminergic pathways, BDNF regulates appetitive behavior (Eisch et al, 2003;Itoh et al, 2004) along with behavioral sensitization to drugs (Guillin et al, 2001) and potentially to palatable food. Through its hypothalamic effects, BDNF controls energy balance by enhancing catabolic processes (Xu et al, 2003). Similarly important are the actions of orexin neurons, situated in the LH and projecting to the NAc and VTA , to control food intake (Edwards et al, 1999;Harris et al, 2005) as well as drug reward and craving (Harris et al, 2005).…”

“…Furthermore, similarly to methadone-maintained patients (Willenbring et al, 1989;Zador et al, 1996), exaggerated opioidergic activity could enhance hedonic preference (ie, liking) for sweet and fatty foods (Doyle et al, 1993;Pecina and Berridge, 1995;. The consumption of these foods further reduces BDNF efficiency in preventing neuronal death (Molteni et al, 2002) and in regulating reward function (Horger et al, 1999;Kernie et al, 2000;Nakagawa et al, 2003), glucose metabolism (Tonra et al, 1999;Nakagawa et al, 2000;Ono et al, 2000), appetitive behaviors (Eisch et al, 2003;Itoh et al, 2004), and other important homeostatic processes (Xu et al, 2003).…”

Y4 receptors and pancreatic polypeptide regulate food intake via hypothalamic orexin and brain-derived neurotropic factor dependent pathways

“…BDNF exerts hypophagic and weight-reducing effects similar to MC4 receptor agonism with α-MSH or synthetic analogues such as MTII (Xu et al, 2003). Melanocortin signaling may mediate effects via the BDNF system, because acute intracerebroventricular injection of MTII led to increased BDNF mRNA expression in the VMH of fasted mice (Xu et al, 2003).…”

Genetic contributors to obesity

“…In humans, profound obesity has been associated with a balanced translocation that disrupts the SIM1 gene (21). Decreased expression of the brain-derived neurotropic factor (BDNF) was reported to affect eating behaviour (22). BDNF and the neurotropic tyrosine kinase receptor B are expressed in the ventromedial hypothalamus and may be downstream effectors of MC4R signalling.…”