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...

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A series of 7 experiments used dual-task methodology to investigate the role of working memory in the operation of a simple action-control plan or program involving regular switching between addition and subtraction. Lists requiring switching were slower than blocked lists and showed 2 concurrent task effects. Demanding executive tasks impaired performance on both blocked and switched lists, whereas articulatory suppression impaired principally the switched condition. Implications for models of task switching and working memory and for the Vygotskian concept of verbal control of action are discussed.