Objective: The aim of this study was to evaluate the effect on body weight set point over time of focused, subnecrotic doses of radiation via gamma knife (GK) to the hypothalamus of the genetically obese Zucker rat. Methods: A total of 36 adolescent animals were used in this experiment and placed in 6 groups of 6. The genetically obese homozygous Zucker rat was used in 4 groups (n = 24) and received GK, subcutaneous cobalt protoporphyrin (CoPP), both treatments combined or sham treatment. The heterozygous lean Zucker rat was used in 2 control groups (n = 12) and received either GK or sham treatment. All animals were weighed at the beginning of the experiment and at weekly intervals for 34 weeks. GK irradiation was accomplished using a specially designed stereotactic frame and a total dose of 40 Gy was given to 2 nearby targets in the medial hypothalamus. The drug subgroups received weekly subcutaneous injections. All animals were housed in the same environment with unlimited access to food. Results: There were no significant differences in weight between the lean GK and sham groups. For the obese cohort, beginning at week 7 and throughout the remainder of the experiment, there were significant and sustained reductions in weight set point for animals that received GK (p < 0.05) and CoPP (p < 0.05) compared to sham-treated animals. Curiously, there was no statistical difference between the combined treatment and sham subgroups, though there was a trend toward weight reduction (p < 0.10). With the exception of one animal in the obese GK cohort in which there was a small area of necrosis lateral to the target area, histopathological analysis failed to reveal any abnormalities. There were no gross behavioral abnormalities noted. Conclusion: Our experimental results suggest that a single dose of GK irradiation to the hypothalamus can produce sustained reduction in the weight set point without emaciation in adolescent animals. The effect of this treatment is comparable to a well-studied drug therapy with a metalloporphyrin. We hypothesize that this involves a resetting of the hypothalamic set point for body weight through an as yet uncharacterized neuromodulatory effect.

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