Low-to-Moderate Dosed Cranial Irradiation in Young Mice Induces Sex-Specific Metabolic Disturbances Later in Life

Survivors of childhood cancers who received high doses (40-60 Gy) of cranial irradiation (CI) have increased risks of developing obesity, type 2 diabetes, and metabolic syndrome (MetS). Here, we subjected mice to CI of 0, 0.5, or 2 Gy directed to the hypothalamus to explore the effects of low-to-moderate doses of CI on MetS risks. Despite targeting the hypothalamus as a major metabolic control center, we did not detect hypothalamic astrocyte or microglia activation at 2 or 7 days, or at 3 months post-CI. Indirect calorimetry at 2 months post-CI showed no metabolic alterations between groups, yet female mice subjected to CI were unresponsive to leptin compared with sham. Follow-up monitoring over 2 years revealed accelerated weight gain in the 2-Gy female group and glucose intolerance in both sexes following CI. Insulin sensitivity, plasma insulin, and triglycerides remained unaltered, but both male and female 2-Gy groups showed elevated VLDL and lowered HDL cholesterol levels and aberrant hypothalamic mRNA levels of genes involved in synaptic and neuronal function, neuroinflammation, and endoplasmic reticulum stress. Mortality remained unaffected by all doses of CI. These data strongly suggest a significant risk for developing MetS following low-to-moderate doses of CI, and they support tailored clinical risk assessment and monitoring strategies for patients undergoing CI, especially when the hypothalamus is included.

High-dose cranial irradiation (CI) during early developmental stages has been linked to metabolic abnormalities in later life, but causal evidence at low-to-moderate doses has been elusive. Monitoring mice for 2 years post-2-Gy CI to the hypothalamus, we found increased risks of leptin resistance, dyslipidemia, glucose intolerance, and weight gain, identifying the hypothalamus as the likely responsible region. Our findings suggest that low-to-moderate doses of CI may be a risk factor for developing metabolic syndrome. Future clinical risk assessment and monitoring strategies are needed for patients undergoing CI of hypothalamic centers governing glucose and energy metabolism.