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Cranial Irradiation Induces Hypothalamic Injury and Late-Onset Metabolic Disturbances in Juvenile Female Rats.

Journal article
Authors Yiran Xu
Yanyan Sun
Kai Zhou
Tao Li
Cuicui Xie
Yaodong Zhang
Juan Rodriguez
Yanling Wu
Min Hu
Linus Ruijin Shao
Xiaoyang Wang
Changlian Zhu
Published in Developmental neuroscience
Volume 40
Issue 2
Pages 120-33
ISSN 1421-9859
Publication year 2018
Published at Institute of Neuroscience and Physiology
Institute of Neuroscience and Physiology, Department of Physiology
Pages 120-33
Language en
Links dx.doi.org/10.1159/000487923
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Basic Medicine

Abstract

Cranial radiotherapy is one of the most effective tools for treating children with brain tumors. However, radiotherapy-induced late-onset side effects have a significant impact on patients' quality of life. The purpose of this study was to investigate the effects of irradiation on metabolism and the possible molecular and cellular mechanisms behind such effects. Female Wistar rats were subjected to a single dose of 6-Gy whole-brain irradiation on postnatal day 11. The animals were sacrificed 6 h or 20 weeks after irradiation. Cell death and proliferation, microglial activation, and inflammation were analyzed and RNA sequencing was performed. We found that irradiation led to a significantly increased body weight from 15 weeks (p < 0.05) along with white adipose tissue accumulation and adipocyte hypertrophy at 20 weeks, and these changes were accompanied by glucose and lipid metabolic disturbances as indicated by reduced glucose tolerance, increased insulin resistance, increased serum triglycerides, and an increased leptin/adiponectin ratio. Furthermore, irradiation induced cell death, microglial activation, inflammation, and persistent astrocyte reactivity in the hypothalamus. Hypothalamic transcriptome analysis showed that 865 genes were downregulated and 290 genes were upregulated in the irradiated group 20 weeks after irradiation, and further pathway analysis showed that the insulin resistance-related PI3K-Akt signaling pathway and the energy expenditure-related adipocytokine signaling pathway were downregulated. Gene Ontology enrichment analysis showed that the expression of fatty acid metabolism-related proteins and effector proteins was significantly different in the irradiation group. This study demonstrates that ionizing radiation to the juvenile female brain induces hypothalamic damage that is likely to be associated with delayed metabolic abnormalities, and this critical vulnerability of the hypothalamus to irradiation should be taken into consideration in the development of future protective strategies for radiotherapy.

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