Environmental activation of a hypothalamic BDNF-adipocyte IL-15 axis regulates adipose-natural killer cells

•Environmental enrichment stimulates expansion of natural killer (NK) cells in fat.•Hypothalamic BDNF is the upstream brain mediator underlying this stimulation.•Adipocyte-derived IL-15 is the downstream mediator of the brain-fat axis.•IL-15 gene transfer to visceral fat expands adipose NK cells and...

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Published in:	Brain, behavior, and immunity Vol. 95; pp. 477 - 488
Main Authors:	Bergin, Stephen M., Xiao, Run, Huang, Wei, Judd, C. Ryan T., Liu, Xianglan, Mansour, Anthony G., Queen, Nicholas, Widstrom, Kyle J., Caligiuri, Michael A., Cao, Lei
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier Inc 01-07-2021
Subjects:	Adipocytes - metabolism Adipose tissue Adipose Tissue - metabolism Animals BDNF Brain-Derived Neurotrophic Factor - metabolism Environmental enrichment Hypothalamus Hypothalamus - metabolism IL-15 Interleukin-15 - metabolism Killer Cells, Natural - metabolism Mice Mice, Inbred C57BL NK cell β-Adrenergic signaling, AAV, cancer β-Adrenergic signaling, AAV, cancer Adipose tissue BDNF Environmental enrichment NK cell IL-15 Hypothalamus
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Summary:	•Environmental enrichment stimulates expansion of natural killer (NK) cells in fat.•Hypothalamic BDNF is the upstream brain mediator underlying this stimulation.•Adipocyte-derived IL-15 is the downstream mediator of the brain-fat axis.•IL-15 gene transfer to visceral fat expands adipose NK cells and inhibits melanoma. Physical and social environments influence immune homeostasis within adipose tissue, yet the mechanisms remain poorly defined. We report that an enriched environment (EE) housing modulates the immune cell population in white adipose tissue of mice including an increase in the abundance of natural killer (NK) cells. EE upregulates the expression of IL-15 and its receptor IL-15Rα specifically within mature adipocytes. Mechanistically, we show that hypothalamic brain-derived neurotrophic factor (BDNF) upregulates IL-15 production in adipocytes via sympathetic β-adrenergic signaling. Overexpressing BDNF mediated by recombinant adeno-associated virus (rAAV) vector in the hypothalamus expands adipose NK cells. Conversely, inhibition of hypothalamic BDNF signaling via gene transfer of a dominant negative TrkB receptor suppresses adipose NK cells. In white adipose tissue, overexpression of IL-15 using an adipocyte-specific rAAV vector stimulates adipose NK cells and inhibits the progression of subcutaneous melanoma, whereas local IL-15 knockdown blocks the EE effect. These results suggest that bio-behavioral factors regulate adipose NK cells via a hypothalamic BDNF-sympathoneural-adipocyte IL-15 axis. Targeting this pathway may have therapeutic significance for cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work S.M.B and R.X designed the studies, carried out the research, interpreted the results, and wrote the manuscript. W.H., X.L., R.T.J., K.J.W., A.G.M., and N.Q., carried out the research. M.A.C. designed the studies, interpreted the results, and revised the manuscript. L.C. designed the studies, interpreted the results, wrote and revised the manuscript. All authors approved the manuscript. Author contributions
ISSN:	0889-1591 1090-2139
DOI:	10.1016/j.bbi.2021.05.005