Hyperphagia, Severe Obesity, Impaired Cognitive Function, and Hyperactivity Associated With Functional Loss of One Copy of the Brain-Derived Neurotrophic Factor (BDNF) Gene

Abstract

The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit increased food intake and obesity, as well as hyperactivity. We report an 8-year-old girl with hyperphagia and severe obesity, impaired cognitive function, and hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. We have identified the proximal inversion breakpoint that lies 850 kb telomeric of the 5 end of the BDNF gene. The patient's genomic DNA was heterozygous for a common coding polymorphism in BDNF, but monoallelic expression was seen in peripheral lymphocytes. Serum concentration of BDNF protein was reduced compared with age-and BMI-matched subjects. Haploinsufficiency for BDNF was associated with increased ad libitum food intake, severe early-onset obesity, hyperactivity, and cognitive impairment. These findings provide direct evidence for the role of the neurotrophin BDNF in human energy homeostasis, as well as in cognitive function, memory, and behavior. Diabetes 55: 3366 -3371, 2006 G enetic studies in patients with severe obesity have established the importance of signaling through the leptin-melanocortin axis in the regulation of human energy homeostasis (1-3). Recently, the concept that hypothalamic neuronal networks involved in energy homeostasis are "hardwired" has been challenged. In mice, hypothalamic neurones projecting from the arcuate nucleus to the paraventricular nucleus develop after birth, and their development is regulated by leptin (4). In addition, synaptic plasticity in the mature rodent brain has been identified as a component of the neuronal regulation of energy homeostasis, as leptin has been shown to acutely modulate excitatory and inhibitory synaptic inputs at the level of first-order arcuate neurones (5). However, it is difficult to establish whether synaptic plasticity plays a role in the physiological regulation of energy homeostasis in humans and whether, under pathological conditions, hypothalamic neuronal networks and plasticity may be impaired and contribute to human obesity.Brain-derived neurotrophic factor (BDNF) regulates the development, survival, and differentiation of neurons through its high-affinity receptor, tropomyosin-related kinase B (TrkB) (6). Unlike other neurotrophins, BDNF is secreted in an activity-dependent manner that allows for highly controlled release (7). Recently, BDNF has been implicated in the regulation of body weight, as its expression is reduced by fasting (8), and BDNF administration causes weight loss in wild-type mice through a reduction in food intake (9). BDNF has also been implicated in memory and a range of behaviors using a number of conditional knockout models (10 -14).To date, no humans have been described with null alleles of BDNF. A common polymorphism in the human BDNF gene, Val66Met (dbSNP no. rs6265), which appears to result in impairment of intracellular trafficking and reduced activity-dependent secretion of BDNF by cultured hip...

Association between brain-derived neurotrophic factor Val66Met and obesity in children and adolescents

“…Likewise, mutations in the genes coding for BDNF and TrkB are responsible for obesity and eating disorders (Lebrun et al, 2006;Noble et al, 2011). Since lower serum or plasma BDNF levels are found in obesity (Araya et al, 2008;El-Gharbawy et al, 2006;Gray et al, 2006;Krabbe et al, 2007;Lommatzsch et al, 2005), compared to normal weight subjects, although opposite results also exist (Bus et al, 2011;Iughetti et al, 2011), our data suggest that carriers of one or two Met alleles in our study had decreased amount of the mature BDNF, possibly lower plasma BDNF levels, and therefore they had higher values of BMI and were more frequently obese. This speculation might be confirmed by the fact that weight gain, induced by antipsychotic drugs, is associated with BDNF serum levels in female schizophrenic patients, while carriers of the Met/Met genotype have lower BDNF levels than carriers of the Val allele (Zhang et al, 2008).…”

“…Its location in the hypothalamic regions such as the paraventricular, arcuate and ventromedial nuclei points to its role in feeding behavior, food intake regulation, energy expenditure, energy homeostasis, glucose homeostasis and weight control (Lebrun et al, 2006;Noble et al, 2011). There are reports of a positive (Bus et al, 2011;Iughetti et al, 2011), as well as inverse relationship (Araya et al, 2008;Gray et al, 2006;Han et al, 2008) and lack of association (Saito et al, 2009), between serum and/or plasma BDNF levels and obesity or BMI. The secretion of the precursor and the mature BDNF protein is affected by the single nucleotide polymorphism (SNP), dbSNP reference number rs6265, in the coding region of exon V of the BDNF gene, located on chromosome 11p13-11p14.…”

Human obesity as a heritable disorder of the central control of energy balance

“…In subsequent years, we and others have shown that human obesity can result from a multiplicity of defects in the downstream pathways of leptin signaling within the brain. 32 These include mutations in the leptin receptor; 33,34 the POMC gene, [35][36][37] which is expressed in hypothalamic cells, which are activated by leptin; in the melanocortin 4 receptor, which is activated by the products of the POMC gene; 38,39 and, much more rarely, defects in signaling systems that are thought to be downstream of the melanocortin 4 receptor, including the brainderived neurotrophic factor 40 and TrkB systems. 41 Most of these defects are rare but molecular defects in the melanocortin 4 receptor are relatively common.…”

Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway

“…Interestingly, high doses of AZ-23 (50 and 100 mg/kg) caused reversible weight gain in mice. Although there are reports implicating the TrkB axis in hyperphagia where inhibition results in overeating and obesity (38)(39)(40), whether AZ-23 impinges directly on this axis have not thus far been investigated further.…”