Neurotrophism and energy homeostasis: perfect together

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Abstract
Energy homeostasis depends upon the balance between anabolic and catabolic drives. Generally, anabolic neuropeptides such as neuropeptide Y (NPY) increase food intake and decrease thermogenesis ([5][1]), while catabolic ones such as α-melanocyte stimulating hormone (α-MSH), which is released from proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (Arc), reduce intake and increase energy expenditure ([32][2]). The companion papers published in this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology by Wang et al. ([62][3], [63][4]) demonstrate that brain-derived neurotrophic factor (BDNF) acts as a prototypic catabolic factor when injected into the hypothalamic paraventricular nucleus (PVN). Food intake is decreased without provoking an aversive reaction, and resting energy expenditure is increased without affecting overall motor activity. These papers are important because they add to the growing body of data that demonstrate unequivocally that BDNF can act at a specific site as a relatively pure catabolic agent ([4][5], [61][6]). They also demonstrate that PVN BDNF injections act with different temporal patterns on energy expenditure and feeding. These findings support others ([2][7]) that demonstrate a divergence of neural pathways originating in the PVN by which energy intake and expenditure are regulated. On the other hand, these studies raise several questions about the regulation of energy homeostasis and the role of BDNF and other neurotrophic factors in this process. ### Why Does a Neurotrophic Factor Affect Energy Homeostasis? There is no factual answer to this question currently available, only observations and speculation. First, are the multiple observations that BDNF, along with many other factors that affect neuronal development, differentiation, survival, and process outgrowth also affect energy homeostasis. All of these are catabolic in their actions and include insulin ([48][8], [49][9], [64][10]), leptin ([7][11], [20][12]), insulin-like growth factor-1 ([60][13]), and ciliary neurotrophic factor ([17][14], [26][15]). Aside from insulin, the others act through JAK/STAT signaling pathways, and all, including insulin, engage MAP kinase, mammalian target of rapamycin, and phosphoinositol-3 kinase as overlapping downstream pathways that converge on a variety of physiologic functions ([15][16], [34][17], [40][18], [52][19], [58][20]). Of particular interest, all share a common effect on activation of the transcription factor, STAT3 ([6][21], [11][22], [15][16], [27][23], [40][18], [46][24]). Insulin appears to exert a particularly important influence on the development of pathways involved in energy homeostasis during the prenatal period ([23][25]). However, in rodents, much of the development of these pathways in the hypothalamus occurs during the first 2–3 wk of postnatal life ([8][26]) during which both insulin and leptin play a dual role. They influence both the development of these pathways ([7][11], [47][27]) and contribute to the regulation of energy homeostasis ([21][28], [55][29]). BDNF is a member of a family of neurotrophins that are functionally separate from leptin and insulin but play similar roles in the regulation of energy homeostasis and in neuronal development, survival, and plasticity. All act through the tyrosine kinase (Trk) family of receptors and BDNF acts specifically at TrkB receptors ([3][30]). BDNF is highly localized in the ventromedial hypothalamic nucleus (VMN), but is also found in the lateral hypothalamic area, dorsomedial nucleus (DMN), and PVN ([54][31]). Its TrkB receptors are found throughout the nervous system in neuronal cell bodies, axons, and dendrites in the cerebral cortex, hippocampus, dentate gyrus, amygdala, striatum, septal nuclei, substantia nigra, cerebellum, motor neurons, brain stem sensory nuclei, and ependymal cells lining the ventricular walls. In the hypothalamus, TrkB is expressed in the PVN, medial preoptic area, supraoptic nucleus, and the mammillary body ([35][32], [66][33]). Its diffuse localization undoubtedly reflects its prominent role as a neurotrophic factor. On the other hand, a regulatory role for BDNF in energy homeostasis was first demonstrated by reduced food intake and body weight gain, which follow chronic systemic and intraventricular BDNF administration to rats ([30][34], [45][35]). Also, BDNF expression in the VMN is increased by intake of a palatable diet ([1][36]) and is decreased by caloric restriction ([65][37]). Although complete deletion of BDNF or TrkB is fatal, partial reductions produce obesity-prone animals that are particularly susceptible to high fat diets ([24][38]). However, these knockout animals are also hyperactive ([24][38]), as are mice infused intraventricularly with BDNF ([38][39]). This reflects the fact that BDNF and its receptors mediate a number of functions, not all of which are directly related to the regulation of energy homeostasis. It also emphasizes the importance of the findings of the studies of Wang et al. ([62][3], [63][4]) demonstrating that the localized injections into the PVN alter energy homeostasis without affecting motor activity. Also, in common with insulin and leptin, BDNF is affected by exercise ([31][40], [42][41]), learning and memory ([36][42]) ([25][43], [44][44]) and stress ([16][45], [54][31], [59][46]). While such observations do not answer the question of why neurotrophic factors might double as regulators of both neuronal development and energy expenditure, they do demonstrate that the regulation of both of these critical physiological functions appears to be a common feature of several families of trophic factors, peptides, and hormones. ### What Are the Downstream Mediators and Pathways of the Thermogenic and Feeding Effects of BDNF? Although Wang et al. ([29][47], [61][6]–[63][4]) have proposed an antagonistic relationship between the anabolic effects of...