Review
Metabolic homeostasis via BDNF and its receptors

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Highlights

  • BDNF signaling plays a significant role from mice to humans in controlling energy homeostasis. Loss of function of BDNF leads to hyperphagia and obesity.

  • BDNF signals through two receptors, TrkB and p75NTR, both of which have been shown to play roles in defined hypothalamic nuclei and cell types in controlling feeding.

  • Many of the feeding roles for p75NTR and TrkB are in opposition, with TrkB suppressing, and p75NTR promoting, feeding.

  • A variant of BDNF, Val66Met, that alters the immature precursor of BDNF, proBDNF, may preferentially activate p75NTR and promote feeding behavior.

  • TrkB and p75NTR, in addition to other neurotrophins, have emerging roles in the periphery, especially in glucose regulation. These roles for TrkB and p75NTR also appear to be functionally opposed.

Metabolic disorders result from dysregulation of central nervous system and peripheral metabolic energy homeostatic pathways. To maintain normal energy balance, neural circuits must integrate feedforward and feedback signals from the internal metabolic environment to orchestrate proper food intake and energy expenditure. These signals include conserved meal and adipocyte cues such as glucose and leptin, respectively, in addition to more novel players including brain-derived neurotrophic factor (BDNF). In particular, BDNF’s two receptors, tropomyosin related kinase B (TrkB) and p75 neurotrophin receptor (p75NTR), are increasingly appreciated to be involved in whole body energy homeostasis. At times, these two receptors even seem to functionally oppose one another’s actions, providing the framework for a potential neurotrophin mediated energy regulatory axis, which we explore further here.

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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