BDNF regulates eating behavior and locomotor activity in mice

Abstract

contributed equally to this work Brain-derived neurotrophic factor (BDNF) was studied initially for its role in sensory neuron development. Ablation of this gene in mice leads to death shortly after birth, and abnormalities have been found in both the peripheral and central nervous systems. BDNF and its tyrosine kinase receptor, TrkB, are expressed in hypothalamic nuclei associated with satiety and locomotor activity. In heterozygous mice, BDNF gene expression is reduced and we find that all heterozygous mice exhibit abnormalities in eating behavior or locomotor activity. We also observe this phenotype in independently derived inbred and hybrid BDNF mutant strains. Infusion with BDNF or NT4/5 can transiently reverse the eating behavior and obesity. Thus, we identify a novel non-neurotrophic function for neurotrophins and indicate a role in behavior that is remarkably sensitive to alterations in BDNF activity. Keywords: brain-derived neurotrophic factor (BDNF)/ hypothalamus/neurotrophins/obesity/TrkB IntroductionIn the last decade, many genes responsible for the signals underlying eating behavior and obesity have been identified. These factors include well described peripheral mediators such as insulin, glucocorticoids and leptin, as well as central mediators that are less well understood (Rosenbaum et al., 1997). The current animal models of obesity focus upon the hypothalamus as the anatomical area within the brain that controls eating behavior. In the 1940s, it was shown that hypothalamic lesions cause hyperphagia and obesity (Hetherington and Ranson, 1942). Today, several genetic models give further insight into the hypothalamus and weight regulation. In the ob and db mouse models, either leptin (ob) or its hypothalamic receptor (db) are mutated and rendered non-functional, resulting in severe early-onset obesity (Coleman, 1978;Caro et al., 1996;Chen et al., 1996;Lee et al., 1996). Overexpression of the agouti peptide or gene-targeted deletion of the hypothalamic receptor it antagonizes, the melanocortin-4 receptor, also result in obesity (Lu et al., 1994;Huszar et al., 1997). Each of these models demonstrates the importance of various specific nuclei within 1290 © European Molecular Biology Organization the hypothalamus including the arcuate, dorsomedial, ventromedial and paraventricular nuclei (Chua et al., 1996;Fan et al., 1997). Additionally, at least two new families of peptides, the orexins and cocaine-and amphetaminerelated transcript (CART), have been localized to the hypothalamus. These factors are thought to mediate feeding behavior in response to neural cues that act upon the satiety centers of the hypothalamus (Kristensen et al., 1998;Sakurai et al., 1998).The neurotrophin (NTF) family is composed of four structurally related proteins with similar functions in promoting neuronal survival within the peripheral nervous system (PNS) (Barde, 1994;Snider, 1998). NTF-deficient mice have been particularly useful in studying nervous system development, as nerve growth factor (NGF), brainderived neurotroph...

Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons

“…The second marker is brain-derived neurotrophic factor (BDNF), which was found previously to mark ventrolateral VMN neurons in adult mice (Kernie et al, 2000). Using mutant mice that harbor lacZ in the BDNF locus (BDNF lacZ ), we observed prominent expression of BDNF lacZ (β-galactosidase) in the ventrolateral region of the anterior and medial VMN of adult mice that overlapped significantly with SF-1, especially in the anterior VMN (Fig.…”

“…However, the obesity phenotype observed in BDNF +/− mice results from hyperphagia and shows incomplete penetrance. Obese BDNF +/− mice exhibit normal locomotor activity, whereas nonobese BDNF +/− mice are thought to counteract this hyperphagia through hyperactivity (Kernie et al, 2000). More recently, conditional inactivation of BDNF in adult mice also resulted in hyperactivity associated with increased anxiety-like behavior (Rios et al, 2001).…”

Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence

“…BDNF-deficient mice exhibited increased eating behavior that was transiently reversed when BDNF was infused. 27 Thus, increased TrkB expression or TrkB-mediated signaling may serve as a negative regulatory pathway involved in food 28 This study has a number of strengths and limitations. We used a relatively large number of SNP markers to capture as much variation as possible across NTRK2.…”

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...…”

“…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).…”