Endocrine Abstracts

The hypothalamo-pituitary–thyroid (HPT) axis serves to maintain appropriate systemic levels of thyroid hormone (TH) through a negative feedback pathway via the hypothalamic arcuate and paraventricular nuclei. However, the effects of TH in other hypothalamic regions are poorly understood. Triiodothyronine (T₃) administration to the hypothalamic ventromedial nucleus (VMN) induces a potent hyperphagic response, although it is unclear whether this is part of a novel physiological pathway or simply an additional component of the HPT axis.

This research investigates the physiological role of TH in the VMN through the use of a recombinant adeno-associated virus (rAAV) designed to locally inactivate TH. Activation and inactivation of TH is mediated by the iodothyonine deiodinases (D1, D2, and D3), where D2 functions to deiodinate tetraiodothyronine (T₄) to produce the active T₃ hormone, and D3 is the inactivating enzyme.

A plasmid encoding D3 cDNA under the control of a CMV promoter was packaged into rAAV to generate a viral titre capable of over-expressing D3 (rAAV-D3). Anaesthetised male Wistar rats received bilateral stereotactic injections of either rAAV-D3 (n=13) or rAAV-GFP (n=11) into the VMN. Both groups were dissected 78 days after surgery.

Over-expression of D3 in rAAV-D3 treated rats was confirmed by QPCR, which demonstrated a 10-fold increase in hypothalamic D3 mRNA (P≤0.001) in comparison to rAAV-GFP controls. Furthermore, the enzymatic activity of D3 was increased in whole hypothalamic samples (P=0.31), whilst D2 activity was unaffected (0.92). This was accompanied by up-regulation of the T₃ transporter, MCT8 (P=0.15), suggesting a reduction in neuronal T₃ content. Plasma levels of free T₃ (P=0.95) and free T₄ (P=0.82) were not altered, however plasma insulin (P=0.38) and leptin (P=0.2) were reduced by rAAV-D3 treatment, thus suggesting that local inactivation of T₃ in the VMN directly modulates peripheral metabolism without affecting the HPT axis.