Trends in Endocrinology & Metabolism
ReviewMetabolic homeostasis via BDNF and its receptors
Section snippets
Connections between body weight homeostasis and neurotrophins
Determinants of body weight such as food intake and energy expenditure are under tight homeostatic control. Insufficient or excess energy states can lead to detrimental effects, including starvation and obesity, respectively. To avoid these consequences, organisms must strongly regulate their food intake to correspond to their energy output [1]. Moreover, they must be responsive to changes in their external energy environment, appropriately recognizing and compensating for changes in food type
BDNF mediated control of energy balance is clinically significant
Following initial studies in mice (Box 1), clinical investigations have identified critical roles for BDNF and TrkB in human energy homeostasis. The first of these was identified in 2004, in a young male who presented with severe obesity due to hyperphagia, along with impairments in short term memory and nociception [16]. Sequencing the functional exons of NTRK2, the gene encoding TrkB, revealed a specific partial loss-of-function mutation in the activation loop of the catalytic domain of the
Neurotrophins control feeding throughout the hypothalamus
It is increasingly recognized that the anatomic origins of many metabolic disorders lie in the brain, specifically within the hypothalamus. This is no exception for the obesity caused by mutations in BDNF and TrkB, nor for the altered feeding of p75NTR mutants. Figure 1 shows schematically, and Table 1 lists, each of the regions of the hypothalamus and the relative expression of BDNF and its receptors according to in situ hybridization data from the Allen Brain Atlas of cells in a given region.
Glucose and insulin homeostasis
While much has been reported about neurotrophins and their receptors in control of feeding and body weight, they also appear to have independent functions in other metabolic systems. For example, BDNF administration to pair-fed diet induced obese mice reveals an improvement in glucose tolerance compared to vehicle treated pair-fed controls [48]. Similarly, pair-feeding and BDNF administration also reduce serum glucose and insulin in obese db/db mice [49]. These results suggest that BDNF
Signaling through p75NTR and TrkB
The determinants of whether BDNF will signal through TrkB or p75NTR in metabolic contexts are currently unknown. While it is plausible that specificity could be determined as a result of cell-type specific expression patterns or the differing affinities with which TrkB (high-affinity) and p75NTR (low-affinity) bind to BDNF, a third possibility exists in the post-translational processing of BDNF. BDNF is first secreted as an immature precursor, proBDNF, which exhibits exclusive binding to
Concluding remarks
We synthesize here a growing body of work delineating that BDNF, and potentially other neurotrophins, can exhibit potent and discriminating effects to regulate energy intake and expenditure through biased action on one of its two receptors. Whereas TrkB exhibits strong anorexigenic effects at baseline, p75NTR appears to function antagonistically as a countermeasure against severe energy deficit. While this is generally supported, further parsing cell-type specific roles for TrkB and p75NTR may
Acknowledgments
We thank the members of the Güler and Deppmann labs for thoughtful conversations around this work, and the reviewers for their helpful insights. This work was supported by a UVA Wagner Fellowship, NIH T32-GM7267-39, and NIH T32-GM7055-45 (to B.P.), Hartwell Foundation Grant (to C.D.D.), and NIH R01-GM121937 (to A.D.G.).
Declaration of interests
No interests are declared.
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