Conditional Deletion Of Brain-Derived Neurotrophic Factor in the Postnatal Brain Leads to Obesity and Hyperactivity

Maribel Rios, Guoping Fan, Csaba Fekete, Joseph Kelly, Brian Bates, Ralf Kuehn, Ronald M. Lechan, Rudolf Jaenisch
2001 Molecular Endocrinology  
Brain-derived neurotrophic factor has been associated previously with the regulation of food intake. To help elucidate the role of this neurotrophin in weight regulation, we have generated conditional mutants in which brain-derived neurotrophic factor has been eliminated from the brain after birth through the use of the cre-loxP recombination system. Brain-derived neurotrophic factor conditional mutants were hyperactive after exposure to stressors and had higher levels of anxiety when evaluated
more » ... in the light/dark exploration test. They also had mature onset obesity characterized by a dra-matic 80-150% increase in body weight, increased linear growth, and elevated serum levels of leptin, insulin, glucose, and cholesterol. In addition, the mutants had an abnormal starvation response and elevated basal levels of POMC, an anorexigenic factor and the precursor for ␣-MSH. Our results demonstrate that brain derived neurotrophic factor has an essential maintenance function in the regulation of anxiety-related behavior and in food intake through central mediators in both the basal and fasted state. (Molecular Endocrinology 15: 1748-1757, 2001) B RAIN-DERIVED NEUROTROPHIC factor (BDNF), a member of the family of neurotrophins, is essential for the survival and maintenance of peripheral sensory neurons (1, 2). Because most Bdnf Ϫ/Ϫ mutants die during the second postnatal week, less is known about the in vivo role of this neurotrophin in the postnatal brain. Previous findings implicated BDNF in weight regulation as exogenous BDNF treatment was demonstrated to cause a reduction in weight and Bdnf ϩ/Ϫ animals show an age-related increase in body weight (3, 4). However, the mode of action of BDNF in weight regulation remains elusive. Through the generation and characterization of several mouse genetic obesity models, a number of central and peripheral factors and their mechanism of action in food intake and metabolic function have been identified. Central regulation of food intake is generally associated with the hypothalamus, where orexigenic factors such as NPY, agouti related protein (AGRP), orexin, and melanin concentrating hormone (MCH) and anorexigenic factors such as cocaine and amphetamine-related transcript, serotonin, TRH, and ␣-MSH are present (5-12). BDNF and its receptor, Trk B, are expressed in various hypothalamic nuclei associated with eating behavior and obesity (3). They are present in neurons in the lateral hypothalamus (feeding center), the ventromedial nucleus (satiety center), and the paraventricular and arcuate nuclei, both of which are required for maintenance of normal body weight. Conclusive evidence that BDNF acts through a central mechanism to regulate weight is still lacking. In addition, it is necessary to establish whether this neurotrophin has a developmental or a maintenance role in weight regulation. To answer some of these questions and to circumvent the problem of early mortality associated with global ablation of the BDNF gene, conditional mutant mice were generated in which BDNF was eliminated in a tissue-and temporalspecific manner using the cre-loxP recombination system (13). Analysis of these mice revealed that BDNF affects locomotor behavior and regulates food intake through a central maintenance mechanism that is independent from its developmental function. RESULTS Generation of Conditional BDNF Mutants LoxP sites were inserted around the single coding exon of BDNF by standard gene targeting techniques Abbreviations: AGRP, Agouti-related protein; BDNF, brainderived neurotrophic factor; CamK, ␣-calcium/calmodulindependent protein kinase II; ES, embryonic stem; MC4-R, melanocortin 4 receptor; MCH, melanin-concentrating hormone.
doi:10.1210/mend.15.10.0706 pmid:11579207 fatcat:6d5rfd2anbh6zdjawadwrifqzi