Journal of Molecular Neuroscience

, Volume 48, Issue 3, pp 654–659 | Cite as

Role of Neurotrophins in the Development and Function of Neural Circuits That Regulate Energy Homeostasis

  • Samira Fargali
  • Masato Sadahiro
  • Cheng Jiang
  • Amy L. Frick
  • Tricia Indall
  • Valeria Cogliani
  • Jelle Welagen
  • Wei-Jye Lin
  • Stephen R. Salton


Members of the neurotrophin family, including nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5, and other neurotrophic growth factors such as ciliary neurotrophic factor and artemin, regulate peripheral and central nervous system development and function. A subset of the neurotrophin-dependent pathways in the hypothalamus, brainstem, and spinal cord, and those that project via the sympathetic nervous system to peripheral metabolic tissues including brown and white adipose tissue, muscle and liver, regulate feeding, energy storage, and energy expenditure. We briefly review the role that neurotrophic growth factors play in energy balance, as regulators of neuronal survival and differentiation, neurogenesis, and circuit formation and function, and as inducers of critical gene products that control energy homeostasis.


Brain-derived neurotrophic factor (BDNF) Corticotropin-releasing hormone (CRH) Hypothalamus Nerve growth factor (NGF) Neurotrophin VGF 


  1. ACTS (1996) A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. ALS CNTF Treatment Study Group. Neurology 46:1244–1249CrossRefGoogle Scholar
  2. Allen TL, Matthews VB, Febbraio MA (2011) Overcoming insulin resistance with ciliary neurotrophic factor. Handb Exp Pharmacol (203):179–199Google Scholar
  3. Bariohay B, Lebrun B, Moyse E, Jean A (2005) Brain-derived neurotrophic factor plays a role as an anorexigenic factor in the dorsal vagal complex. Endocrinology 146:5612–5620PubMedCrossRefGoogle Scholar
  4. Bariohay B, Roux J, Tardivel C, Trouslard J, Jean A, Lebrun B (2009) Brain-derived neurotrophic factor/tropomyosin-related kinase receptor type B signaling is a downstream effector of the brainstem melanocortin system in food intake control. Endocrinology 150:2646–2653PubMedCrossRefGoogle Scholar
  5. Bartolomucci A, Possenti R, Mahata SK, Fischer-Colbrie R, Loh YP, Salton SR (2011) The extended granin family: structure, function, and biomedical implications. Endocr Rev 32:755–797PubMedCrossRefGoogle Scholar
  6. Bozdagi O, Rich E, Tronel S et al (2008) The neurotrophin-inducible gene Vgf regulates hippocampal function and behavior through a brain-derived neurotrophic factor-dependent mechanism. J Neurosci 28:9857–9869PubMedCrossRefGoogle Scholar
  7. Cao L, Choi EY, Liu X et al (2011) White to brown fat phenotypic switch induced by genetic and environmental activation of a hypothalamic–adipocyte axis. Cell Metab 14:324–338PubMedCrossRefGoogle Scholar
  8. Chaldakov GN, Tonchev AB, Aloe L (2009) NGF and BDNF: from nerves to adipose tissue, from neurokines to metabokines. Riv Psichiatr 44:79–87PubMedGoogle Scholar
  9. Collins S, Cao W, Robidoux J (2004) Learning new tricks from old dogs: beta-adrenergic receptors teach new lessons on firing up adipose tissue metabolism. Mol Endocrinol 18:2123–2131PubMedCrossRefGoogle Scholar
  10. Dallman MF, la Fleur SE, Pecoraro NC, Gomez F, Houshyar H, Akana SF (2004) Minireview: Glucocorticoids—food intake, abdominal obesity, and wealthy nations in 2004. Endocrinology 145:2633–2638PubMedCrossRefGoogle Scholar
  11. Glebova NO, Ginty DD (2004) Heterogeneous requirement of NGF for sympathetic target innervation in vivo. J Neurosci 24:743–751PubMedCrossRefGoogle Scholar
  12. Glebova NO, Ginty DD (2005) Growth and survival signals controlling sympathetic nervous system development. Annu Rev Neurosci 28:191–222PubMedCrossRefGoogle Scholar
  13. Hahm S, Mizuno TM, Wu TJ et al (1999) Targeted deletion of the Vgf gene indicates that the encoded secretory peptide precursor plays a novel role in the regulation of energy balance. Neuron 23:537–548PubMedCrossRefGoogle Scholar
  14. Hahm S, Fekete C, Mizuno TM et al (2002) VGF is required for obesity induced by diet, gold thioglucose treatment and agouti, and is differentially regulated in POMC- and NPY-containing arcuate neurons in response to fasting. J Neurosci 22:6929–6938PubMedGoogle Scholar
  15. Harrington AW, St Hillaire C, Zweifel LS et al (2011) Recruitment of actin modifiers to TrkA endosomes governs retrograde NGF signaling and survival. Cell 146:421–434PubMedCrossRefGoogle Scholar
  16. Holtmann B, Wiese S, Samsam M et al (2005) Triple knock-out of CNTF, LIF, and CT-1 defines cooperative and distinct roles of these neurotrophic factors for motoneuron maintenance and function. J Neurosci 25:1778–1787PubMedCrossRefGoogle Scholar
  17. Honma Y, Araki T, Gianino S et al (2002) Artemin is a vascular-derived neurotropic factor for developing sympathetic neurons. Neuron 35:267–282PubMedCrossRefGoogle Scholar
  18. Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736PubMedCrossRefGoogle Scholar
  19. Jeanneteau FD, Lambert WM, Ismaili N et al (2012) BDNF and glucocorticoids regulate corticotrophin-releasing hormone (CRH) homeostasis in the hypothalamus. Proc Natl Acad Sci U S A 109:1305–1310PubMedCrossRefGoogle Scholar
  20. Kernie SG, Liebl DJ, Parada LF (2000) BDNF regulates eating behavior and locomotor activity in mice. EMBO J 19:1290–1300PubMedCrossRefGoogle Scholar
  21. Kokoeva MV, Yin H, Flier JS (2005) Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science 310:679–683PubMedCrossRefGoogle Scholar
  22. Kuruvilla R, Zweifel LS, Glebova NO et al (2004) A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signaling. Cell 118:243–255PubMedCrossRefGoogle Scholar
  23. Lapchak PA, Hefti F (1992) BDNF and NGF treatment in lesioned rats: effects on cholinergic function and weight gain. Neuroreport 3:405–408PubMedCrossRefGoogle Scholar
  24. Levi A, Eldridge JD, Paterson BM (1985) Molecular cloning of a gene sequence regulated by nerve growth factor. Science 229:393–395PubMedCrossRefGoogle Scholar
  25. Levi A, Ferri GL, Watson E, Possenti R, Salton SR (2004) Processing, distribution and function of VGF, a neuronal and endocrine peptide precursor. Cell Mol Neurobiol 24:517–533PubMedCrossRefGoogle Scholar
  26. Levin BE (2007) Neurotrophism and energy homeostasis: perfect together. Am J Physiol Regul Integr Comp Physiol 293:R988–R991PubMedCrossRefGoogle Scholar
  27. Liao GY, An JJ, Gharami K et al (2012) Dendritically targeted Bdnf mRNA is essential for energy balance and response to leptin. Nat Med 18:564–571PubMedCrossRefGoogle Scholar
  28. Matthews VB, Febbraio MA (2008) CNTF: a target therapeutic for obesity-related metabolic disease? J Mol Med (Berl) 86:353–361CrossRefGoogle Scholar
  29. Miller RG, Petajan JH, Bryan WW et al (1996) A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group. Ann Neurol 39:256–260PubMedCrossRefGoogle Scholar
  30. Nakagawa T, Tsuchida A, Itakura Y et al (2000) Brain-derived neurotrophic factor regulates glucose metabolism by modulating energy balance in diabetic mice. Diabetes 49:436–444PubMedCrossRefGoogle Scholar
  31. Noble EE, Billington CJ, Kotz CM, Wang C (2011) The lighter side of BDNF. Am J Physiol Regul Integr Comp Physiol 300:R1053–R1069PubMedCrossRefGoogle Scholar
  32. Pelleymounter MA, Cullen MJ, Wellman CL (1995) Characteristics of BDNF-induced weight loss. Exp Neurol 131:229–238PubMedCrossRefGoogle Scholar
  33. Possenti R, Muccioli G, Petrocchi P et al (2012) Characterization of a novel peripheral pro-lipolytic mechanism in mice: role of VGF-derived peptide TLQP-21. Biochem J 441:511–522PubMedCrossRefGoogle Scholar
  34. Rios M, Fan G, Fekete C et al (2001) Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol Endocrinol 15:1748–1757PubMedCrossRefGoogle Scholar
  35. Seeley RJ (2005) More neurons, less weight. Nat Med 11:1276–1278PubMedCrossRefGoogle Scholar
  36. Singh KK, Park KJ, Hong EJ et al (2008) Developmental axon pruning mediated by BDNF-p75NTR-dependent axon degeneration. Nat Neurosci 11:649–658PubMedCrossRefGoogle Scholar
  37. Suwa M, Kishimoto H, Nofuji Y et al (2006) Serum brain-derived neurotrophic factor level is increased and associated with obesity in newly diagnosed female patients with type 2 diabetes mellitus. Metabolism 55:852–857PubMedCrossRefGoogle Scholar
  38. Tapia-Arancibia L, Rage F, Givalois L, Arancibia S (2004) Physiology of BDNF: focus on hypothalamic function. Front Neuroendocrinol 25:77–107PubMedCrossRefGoogle Scholar
  39. Thakker-Varia S, Krol JJ, Nettleton J et al (2007) The neuropeptide VGF produces antidepressant-like behavioral effects and enhances proliferation in the hippocampus. J Neurosci 27:12156–12167PubMedCrossRefGoogle Scholar
  40. Toriya M, Maekawa F, Maejima Y et al (2010) Long-term infusion of brain-derived neurotrophic factor reduces food intake and body weight via a corticotrophin-releasing hormone pathway in the paraventricular nucleus of the hypothalamus. J Neuroendocrinol 22:987–995PubMedCrossRefGoogle Scholar
  41. Toshinai K, Yamaguchi H, Kageyama H et al (2010) Neuroendocrine regulatory peptide-2 regulates feeding behavior via the orexin system in the hypothalamus. Am J Physiol Endocrinol Metab 299:E394–E401PubMedCrossRefGoogle Scholar
  42. Tsuchida A, Nakagawa T, Itakura Y et al (2001) The effects of brain-derived neurotrophic factor on insulin signal transduction in the liver of diabetic mice. Diabetologia 44:555–566PubMedCrossRefGoogle Scholar
  43. Tsuchida A, Nonomura T, Nakagawa T et al (2002) Brain-derived neurotrophic factor ameliorates lipid metabolism in diabetic mice. Diabetes Obes Metab 4:262–269PubMedCrossRefGoogle Scholar
  44. Turtzo LC, Marx R, Lane MD (2001) Cross-talk between sympathetic neurons and adipocytes in coculture. Proc Natl Acad Sci U S A 98:12385–12390PubMedCrossRefGoogle Scholar
  45. Unger TJ, Calderon GA, Bradley LC, Sena-Esteves M, Rios M (2007) Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behavior and obesity. J Neurosci 27:14265–14274PubMedCrossRefGoogle Scholar
  46. Wang C, Bomberg E, Levine A, Billington C, Kotz CM (2007a) Brain-derived neurotrophic factor in the ventromedial nucleus of the hypothalamus reduces energy intake. Am J Physiol Regul Integr Comp Physiol 293:R1037–R1045PubMedCrossRefGoogle Scholar
  47. Wang C, Bomberg E, Billington C, Levine A, Kotz CM (2007b) Brain-derived neurotrophic factor in the hypothalamic paraventricular nucleus reduces energy intake. Am J Physiol Regul Integr Comp Physiol 293:R1003–R1012PubMedCrossRefGoogle Scholar
  48. Wang C, Bomberg E, Billington C, Levine A, Kotz CM (2007c) Brain-derived neurotrophic factor in the hypothalamic paraventricular nucleus increases energy expenditure by elevating metabolic rate. Am J Physiol Regul Integr Comp Physiol 293:R992–R1002PubMedCrossRefGoogle Scholar
  49. Watson E, Hahm S, Mizuno TM et al (2005) VGF ablation blocks the development of hyperinsulinemia and hyperglycemia in several mouse models of obesity. Endocrinology 146:5151–5163PubMedCrossRefGoogle Scholar
  50. Watson E, Fargali S, Okamoto H et al (2009) Analysis of knockout mice suggests a role for VGF in the control of fat storage and energy expenditure. BMC Physiol 9:19PubMedCrossRefGoogle Scholar
  51. Xu B, Goulding EH, Zang K et al (2003) Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci 6:736–742PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Samira Fargali
    • 1
  • Masato Sadahiro
    • 1
  • Cheng Jiang
    • 1
  • Amy L. Frick
    • 1
  • Tricia Indall
    • 1
  • Valeria Cogliani
    • 1
  • Jelle Welagen
    • 1
  • Wei-Jye Lin
    • 1
  • Stephen R. Salton
    • 1
    • 2
    • 3
    • 4
  1. 1.Fishberg Department of NeuroscienceMount Sinai School of MedicineNew YorkUSA
  2. 2.Brookdale Department of Geriatrics and Palliative MedicineMount Sinai School of MedicineNew YorkUSA
  3. 3.Friedman Brain InstituteMount Sinai School of MedicineNew YorkUSA
  4. 4.Department of NeuroscienceMount Sinai School of MedicineNew YorkUSA

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