Effects of Ketogenic Diet on Behavioral, Metabolic, and Peripheral Tissue Changes in a Propylthiouracil-Induced Hypothyroidism Model

OBJECTIVE: This study aimed to evaluate whether a ketogenic diet (KD) mitigates behavioral, metabolic, and peripheral tissue alterations in a rat model of propylthiouracil (PTU)-induced hypothyroidism. SUBJECTS AND METHODS: Adult female Sprague-Dawley rats (n = 28) were randomly assigned to Control, KD, PTU, and KD+PTU groups. Hypothyroidism was induced using 0.05% PTU for six weeks, while KD was administered during the final four weeks. Behavioral testing was conducted during the final phase of the experimental period, followed by biochemical and histological analyses at the end of the six-week protocol. Behavioral assessments included the open field, light/dark box, forced swim, and Morris water maze tests. Biochemical analyses evaluated serum free thyroxine (T4), thyroid-stimulating hormone (TSH), glucose, β-hydroxybutyrate, tumor necrosis factor alpha (TNF-α), and interleukin 10 (IL-10). Histological evaluations targeted the thyroid gland, liver, white adipose tissue, and brown adipose tissue. RESULTS: PTU significantly reduced serum free T4 levels and impaired spatial learning and mood-related behaviors. KD effectively induced nutritional ketosis and improved systemic glucose metabolism but did not reverse cognitive impairment or depressive-like behaviors associated with hypothyroidism. Histologically, KD attenuated PTU-induced hepatic inflammation, white adipose tissue dysfunction, and brown adipose tissue whitening. Thyroid morphology and circulating TNF-α and IL-10 levels remained unchanged across groups. CONCLUSION: KD exerts favorable metabolic and peripheral tissue effects in PTU-induced hypothyroidism but does not rescue associated neurobehavioral deficits, likely due to persistent thyroid hormone deficiency.