Low-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-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, nor 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 to 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 V-LDL and lowered HDL levels and aberrant hypothalamic mRNA levels of genes involved in synaptic and neuronal function, neuroinflammation and ER 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 support tailored clinical risk assessment and monitoring strategies for patients undergoing CI, especially when the hypothalamus is included.