The hypothalamo-pituitarythyroid (HPT) axis maintains controlled systemic levels of thyroid hormone (TH). This is achieved through negative feedback via the hypothalamic arcuate and paraventricular nuclei. The effects of thyroid hormone in other hypothalamic nuclei are yet to be elucidated. Administration of triiodothyronine (T3, thyroid hormone) into the hypothalamic ventromedial nucleus (VMN) increases food intake in rats. Thyroid hormone activation and inactivation is mediated by the iodothyronine deiodinases (D1, D2 and D3). D2 deiodinates tetraiodothyronine (T4) to produce the active T3 hormone, whilst D3 is the principal inactivating hormone.
Recombinant adeno-associated virus (rAAV) constitutively expressing D3 (rAAV-D3) was used to overexpress D3. Male Wistar rats received either rAAV-D3 (n=10) or rAAV-green fluorescent protein (rAVV-GFP) as a control (n=11) bilaterally in the VMN. On day 17 post-surgery, animals were transferred from a normal chow diet (NFD) onto a 60% fat diet (HFD), and the study continued until 72 days post-surgery.
Hypothalamic D3 mRNA was 10-fold higher following treatment with rAAV-D3 compared to the rAAV-GFP treated group (P<0.001). Plasma free T3 and free T4, however, were unchanged, indicating that systemic thyroid hormone status was unaffected.
These data confirm an increase in hypothalamic D3 following rAAV-D3 administration into the rat VMN. This model is currently undergoing extensive metabolic phenotyping in order to determine the effects of T3 inactivation in the VMN on energy homeostasis.