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Brain-Derived Neurotrophic Factors and Obesity in WAGR Syndrome

« Back to Volume 25, Issue 1, June 2009 - Table of Contents

The syndrome of Wilms’ tumor, aniridia, anomalies of the genitourinary tract including ambiguous external genitalia, mental retardation and hemihypertrophy (WAGR - OMIM 194072, chromosome 11p13, Figures 1 and 2) is associated with heterozygous microdeletions of chromosome 11p13 and loss of the contiguous genes WT1 (OMIM 607102) and PAX6 (OMIM 607108). Obesity has been found in some subjects with this disorder. Also on chromosome 11p13 is the neuronal survival factor, brain-derived neurotrophic factor (BDNF, OMIM 113505), which has been found to affect energy metabolism in rodents. Loss of Bdnf in mice results in excessive weight gain in adulthood due to increased caloric intake.¹ Thus, BDNF may be an anorexigenic factor. In order to examine the effect of BDNF on energy metabolism in humans, the investigators examined the relationship between the presence or absence of BDNF and weight in patients with WAGR by examining the extent of the deletion at chromosome 11p13 in 33 patients. Haploinsufficiency of BDNF was present in 19 patients–complete in 17 and partial in 2 subjects. By 2 years of age, weight was greater in all WAGR patients with loss of BDNF than in those with an intact gene. Serum concentrations of BDNF were higher and hyperphagia was more prevalent in the former subjects. Loss of any exon of BDNF or of a portion of the 70 to 80-kb region upstream of BDNF was associated with obesity. The investigators also demonstrated that heterozygous loss of BDNF was associated with decreased pain perception in WAGR subjects. The authors concluded that BDNF modulates appetite in humans as well as in experimental animals.

Figure 1. Genetic Loci on Chromosome 11 in Patients with the WAGR Syndrome.
The WAGR syndrome is caused by deletions on chromosome 11p that result in haploinsufficiency for the PAX6 and WT1 genes. BDNF is located approximately 4 Mb telomeric to PAX6.

Figure 2. Regions of Deletion on Chromosome 11p.
The region of deletion on chromosome 11p is shown for each of the 24 patients in whom the presence or absence of childhood obesity (body-mass index [BMI] ±95th percentile by 10 years of age) could be determined. No association between the centromeric deletion boundary and childhood obesity was observed. However, for the telomeric deletion boundary, all patients with heterozygous deletion of all or a portion of BDNF had childhood obesity, whereas no deletions involved BDNF in the patients who were of normal weight. In Patient 1, who was obese, there was a heterozygous deletion of BDNF exons 1 through 3. In Patient 2, who had a normal weight (BMI, approximately 20th percentile at 10 years of age), the deletion region ended 72.5 kb upstream of BDNF. Only 20% of the patients without BDNF deletions were obese; this rate is similar to the prevalence of childhood obesity in the general U.S. population.⁶

Han JC, Liu QR, Jones MP, et al. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med. 2008;359:918-927.

Editor’s Comment

These observations suggest that there well may be patients with childhood onset obesity and loss-of-function mutations in BDNF itself or in its 5’ region and/or that a polymorphic variant(s) of this gene may be related to appetite, caloric intake, and body weight. In the hierarchal mechanisms that regulate appetite, BDNF may function downstream of the melanocortin 4 receptor and thus be responsive to the effects of αMSH and proopiomelanocortin.² Other clinical studies have demonstrated a strong association between the BDNF Met66 allele of the Val66Met polymorphic variant and anorexia nervosa and other eating disorders.³ Interestingly, the Val66 allele of BDNF has been associated with child onset bipolar disorder.⁴ The model of the anorectic action of BNDF in the hypothalamus⁵ is shown in Figure 3.

Allen W. Root, MD

Figure 3. Model of the Anorectic Action of Brain-Derived Neurotrophic Factor (BDNF) in the Hypothalamus.
BDNF is produced by thyrotropin-releasing hormone neurons in the paraventricular nucleus and acts on neurotrophic tyrosine kinase receptor type 2 (TrkB). BDNF-producing neurons are excited by the release of α-melanocyte–stimulating hormone (α-MSH) from proopiomelanocortin (POMC) neurons in the arcuate nucleus, which acts on melanocortin 4 receptors (MC4Rs). BDNF-producing neurons in the paraventricular nucleus are inhibited by neuropeptide Y that is released from the arcuate nucleus. Leptin from the periphery can also excite BDNF-producing neurons that express the signaling form of the leptin receptor. Adapted from Levin.⁷

Reference - (linked to )

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Last Updated: 2/2/2011