Triiodothyronine stimulates food intake via the hypothalamic ventromedial nucleus independent of changes in energy expenditure

Increased food intake is characteristic of hyperthyroidism, although this is presumed to compensate for a state of negative energy balance. However, here we show that the thyroid hormone T-3 directly stimulates feeding at the level of the hypothalamus. Peripheral administration of T-3 doubled food intake in ad libitum-fed rats over 2 h and induced expression of the immediate early gene, early growth response-1, in the hypothalamic ventromedial nucleus (VMN), whereas maintaining plasma-free T-3 levels within the normal range. T-3-induced feeding occurred without altering energy expenditure or locomotion. Injection of T-3 directly into the VMN produced a 4-fold increase in food intake in the first hour. The majority of T-3 in the brain is reported to be produced by tissue-specific conversion of T-4 to T-3 by the enzyme type 2 iodothyronine deiodinase (D2). Hypothalamic D2 mRNA expression showed a diurnal variation, with a peak in the nocturnal feeding phase. Hypothalamic D2 mRNA levels also increased after a 12- and 24-h fast, suggesting that local production of T-3 may play a role in this T-3 feeding circuit. Thus, we propose a novel hypothalamic feeding circuit in which T-3, from the peripheral circulation or produced by local conversion, stimulates food intake via the VMN.