Selective Deletion ofBdnfin the Ventromedial and Dorsomedial Hypothalamus of Adult Mice Results in Hyperphagic Behavior and Obesity

Abstract

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are expressed in several hypothalamic and hindbrain nuclei involved in regulating energy homeostasis, developmentally and in the adult animal. Their depletion during the fetal or early postnatal periods when developmental processes are still ongoing elicits hyperphagic behavior and obesity in mice. Whether BDNF is a chief element in appetite control in the mature brain remains controversial. The required sources of this neurotrophin are also unknown. We show that glucose administration rapidly induced BDNF mRNA expression, mediated by Bdnf promoter 1, and TrkB transcription in the ventromedial hypothalamus (VMH) of adult mice, consistent with a role of this pathway in satiety. Using viral-mediated selective knock-down of BDNF in the VMH and dorsomedial hypothalamus (DMH) of adult mice, we were able to elucidate the physiological relevance of BDNF in energy balance regulation. Site-specific mutants exhibited hyperphagic behavior and obesity but normal energy expenditure. Furthermore, intracerebroventricular administration of BDNF triggered an immediate neuronal response in multiple hypothalamic nuclei in wild-type mice, suggesting that its anorexigenic actions involve short-term mechanisms. Locomotor, aggressive, and depressive-like behaviors, all of which are associated with neural circuits involving the VMH, were not altered in VMH/DMH-specific BDNF mutants. These findings demonstrate that BDNF is an integral component of central mechanisms mediating satiety in the adult mouse and, moreover, that its synthesis in the VMH and/or DMH is required for the suppression of appetite.

Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling

“…Interestingly, disruption from promoters I and II prominently impaired BDNF expression in HYP, raising the possibility that BDNF produced from these promoters contributes to development of hypothalamic circuits that mediate aggression. This is consistent with previous studies demonstrating that Ex1 and Ex2 transcripts are highly expressed and regulated in the HYP (Han et al, 2008;Unger et al, 2007). Of all brain areas, HYP is the beststudied in relation to aggression and has been directly implicated in attack behavior (Lin et al, 2011;Woodworth, 1971).…”

The "selfish brain" hypothesis for metabolic abnormalities in bipolar disorder and schizophrenia

“…75 In the hypothalamus, BDNF expression was shown to be inhibited by dietary restriction and enhanced by energy availability, especially glucose. 76,77 Moreover, diminished BDNF expression produced hyperphagia and obesity in an animal model. 77,78 Could all these metabolic abnormalities described in schizophrenia and BD be better explained by adopting a single and comprehensive paradigm?…”

“…76,77 Moreover, diminished BDNF expression produced hyperphagia and obesity in an animal model. 77,78 Could all these metabolic abnormalities described in schizophrenia and BD be better explained by adopting a single and comprehensive paradigm? The selfish brain theory provides a cohesive conceptual framework for answering that question.…”

Treating Diet-Induced Obesity: A New Role for Vagal Afferents?

“…High-energy diets can reduce the levels of anorexigens in CNS nuclei that regulate feeding and body weight [21]; in some instances these reductions contribute to hyperphagia and obesity [22]. Thus, if the high-energy diets fed to the neurotrophin-4 mutants or the DIO rats of Stearns et al [8] reduced anorexigen levels in key CNS nuclei, then these reductions, combined with the effects of the missing vagal GI afferents, may have produced long-term effects on food intake and abdominal fat.…”