Environmental and Genetic Activation of a Brain-adipocyte BDNF/leptin Axis Causes Cancer Remission and Inhibition

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2010 Jul 7

PMID 20603014

Citations 157

Authors

Lei Cao

Xianglan Liu

En-Ju D Lin

Chuansong Wang

Eugene Y Choi

Veronique Riban

Benjamin Lin

Matthew J During

Affiliations

Soon will be listed here.

Abstract

Cancer is influenced by its microenvironment, yet broader, environmental effects also play a role but remain poorly defined. We report here that mice living in an enriched housing environment show reduced tumor growth and increased remission. We found this effect in melanoma and colon cancer models, and that it was not caused by physical activity alone. Serum from animals held in an enriched environment (EE) inhibited cancer proliferation in vitro and was markedly lower in leptin. Hypothalamic brain-derived neurotrophic factor (BDNF) was selectively upregulated by EE, and its genetic overexpression reduced tumor burden, whereas BDNF knockdown blocked the effect of EE. Mechanistically, we show that hypothalamic BDNF downregulated leptin production in adipocytes via sympathoneural beta-adrenergic signaling. These results suggest that genetic or environmental activation of this BDNF/leptin axis may have therapeutic significance for cancer.

Citing Articles

Gut dysbiosis conveys psychological stress to activate LRP5/β-catenin pathway promoting cancer stemness.

Cui B, Luo H, He B, Liu X, Lv D, Zhang X Signal Transduct Target Ther. 2025; 10(1):79.

PMID: 40038255 PMC: 11880501. DOI: 10.1038/s41392-025-02159-1.

Upregulation of . in gut microbiota as a novel mechanism for environmental eustress-induced anti-pancreatic cancer effects.

Liang Y, Du M, Li X, Gao J, Li Q, Li H Gut Microbes. 2025; 17(1):2470372.

PMID: 39988618 PMC: 11853549. DOI: 10.1080/19490976.2025.2470372.

Neuroscience of cancer: unraveling the complex interplay between the nervous system, the tumor and the tumor immune microenvironment.

Huang Q, Hu B, Zhang P, Yuan Y, Yue S, Chen X Mol Cancer. 2025; 24(1):24.

PMID: 39825376 PMC: 11740516. DOI: 10.1186/s12943-024-02219-0.

Remodeling the Epigenome Through Meditation: Effects on Brain, Body, and Well-being.

Venditti S Subcell Biochem. 2025; 108():231-260.

PMID: 39820865 DOI: 10.1007/978-3-031-75980-2_7.

Environmental Enrichment Normalizes Metabolic Function in the Murine Model of Prader-Willi Syndrome Magel2-Null Mice.

Queen N, Zou X, Huang W, Mohammed T, Cao L Endocrinology. 2025; 166(3).

PMID: 39801003 PMC: 11808065. DOI: 10.1210/endocr/bqaf001.

References

Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K . Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A. 1993; 90(8):3539-43. PMC: 46336. DOI: 10.1073/pnas.90.8.3539. View

Rios M, Fan G, Fekete C, Kelly J, Bates B, Kuehn R . Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol Endocrinol. 2001; 15(10):1748-57. DOI: 10.1210/mend.15.10.0706. View

McDougall S, Widdop R, Lawrence A . Central autonomic integration of psychological stressors: focus on cardiovascular modulation. Auton Neurosci. 2005; 123(1-2):1-11. DOI: 10.1016/j.autneu.2005.09.005. View

Nedivi E, Hevroni D, Naot D, Israeli D, Citri Y . Numerous candidate plasticity-related genes revealed by differential cDNA cloning. Nature. 1993; 363(6431):718-22. DOI: 10.1038/363718a0. View

Hahn S, Haselhorst U, Quadbeck B, Tan S, Kimmig R, Mann K . Decreased soluble leptin receptor levels in women with polycystic ovary syndrome. Eur J Endocrinol. 2006; 154(2):287-94. DOI: 10.1530/eje.1.02078. View

Xu B, Goulding E, Zang K, Cepoi D, Cone R, Jones K . Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci. 2003; 6(7):736-42. PMC: 2710100. DOI: 10.1038/nn1073. View

Larsson F, Winblad B, Mohammed A . Psychological stress and environmental adaptation in enriched vs. impoverished housed rats. Pharmacol Biochem Behav. 2002; 73(1):193-207. DOI: 10.1016/s0091-3057(02)00782-7. View

Lu Y, Lou Y, Nolan B, Peng Q, Xie J, Wagner G . Stimulatory effect of voluntary exercise or fat removal (partial lipectomy) on apoptosis in the skin of UVB light-irradiated mice. Proc Natl Acad Sci U S A. 2006; 103(44):16301-6. PMC: 1637577. DOI: 10.1073/pnas.0607789103. View

Cao L, Lin E, Cahill M, Wang C, Liu X, During M . Molecular therapy of obesity and diabetes by a physiological autoregulatory approach. Nat Med. 2009; 15(4):447-54. PMC: 3900280. DOI: 10.1038/nm.1933. View

10.

Jenkins P, Bustin S . Evidence for a link between IGF-I and cancer. Eur J Endocrinol. 2004; 151 Suppl 1:S17-22. DOI: 10.1530/eje.0.151s017. View

11.

Bariohay B, Lebrun B, Moyse E, Jean A . Brain-derived neurotrophic factor plays a role as an anorexigenic factor in the dorsal vagal complex. Endocrinology. 2005; 146(12):5612-20. DOI: 10.1210/en.2005-0419. View

12.

Bartness T, Song C . Brain-adipose tissue neural crosstalk. Physiol Behav. 2007; 91(4):343-51. PMC: 1986714. DOI: 10.1016/j.physbeh.2007.04.002. View

13.

Wauters M, Considine R, Van Gaal L . Human leptin: from an adipocyte hormone to an endocrine mediator. Eur J Endocrinol. 2000; 143(3):293-311. DOI: 10.1530/eje.0.1430293. View

14.

Naert G, Ixart G, Tapia-Arancibia L, Givalois L . Continuous i.c.v. infusion of brain-derived neurotrophic factor modifies hypothalamic-pituitary-adrenal axis activity, locomotor activity and body temperature rhythms in adult male rats. Neuroscience. 2006; 139(2):779-89. DOI: 10.1016/j.neuroscience.2005.12.028. View

15.

Su L, Kinzler K, Vogelstein B, Preisinger A, Moser A, Luongo C . Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science. 1992; 256(5057):668-70. DOI: 10.1126/science.1350108. View

16.

Unger T, Calderon G, Bradley L, Sena-Esteves M, Rios M . Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behavior and obesity. J Neurosci. 2007; 27(52):14265-74. PMC: 6673437. DOI: 10.1523/JNEUROSCI.3308-07.2007. View

17.

Fujisawa T, Endo H, Tomimoto A, Sugiyama M, Takahashi H, Saito S . Adiponectin suppresses colorectal carcinogenesis under the high-fat diet condition. Gut. 2008; 57(11):1531-8. PMC: 2582344. DOI: 10.1136/gut.2008.159293. View

18.

Dhillo W . Appetite regulation: an overview. Thyroid. 2007; 17(5):433-45. DOI: 10.1089/thy.2007.0018. View

19.

Cirillo D, Rachiglio A, La Montagna R, Giordano A, Normanno N . Leptin signaling in breast cancer: an overview. J Cell Biochem. 2008; 105(4):956-64. DOI: 10.1002/jcb.21911. View

20.

Darnell R, Posner J . Paraneoplastic syndromes affecting the nervous system. Semin Oncol. 2006; 33(3):270-98. DOI: 10.1053/j.seminoncol.2006.03.008. View