The Role of Thyroid Hormone in the Ventromedial Nucleus of the Hypothalamus

Abstract

The hypothalamic arcuate and paraventricular nuclei play important roles in the neuroendocrine regulation of systemic thyroid hormone homeostasis. However, the roles of other hypothalamic regions are poorly understood. Triiodothyronine (T3) is the active form of thyroid hormone. T3 administration to the hypothalamic ventromedial nucleus (VMN) of rats stimulates feeding, although the mechanism remains unclear. Activation and inactivation of thyroid hormones is mediated by the iodothyonine deiodinases, where D2 is the activating enzyme and D3 the inactivating enzyme. Recombinant adeno-associated virus (rAAV) vectors were designed to modulate the local activity of thyroid hormones by over-expressing D2 (rAAV-D2) or D3 (rAAV-D3). Two initial investigations were carried out employing these viruses in vivo. Initially, rats received bilateral injections of either rAAV-D2 or rAAV-GFP into the VMN. Cumulative food intake and body weight were unaffected, despite a significant increase D2 enzyme activity. However, fasted rAAV-D2 treated rats consumed significantly more food than controls over the initial 2 hours of refeeding following a 12 fast. In the second investigation, rats received bilateral injections of either rAAV-D3 or rAAV-GFP into the VMN. Hypothalamic D3 mRNA and brown adipose tissue activity were both significantly increased in the rAAV-D3 group, which was not associated with any change in systemic thyroid hormone levels. This suggested that sympathetic activity had been increased, independent of peripheral thyroid status. In a final investigation, rats were challenged with a high fat diet (HFD) 17 days after iVMN injection of either rAAV-D3 or rAAV-GFP. The rAAV-D3 treated group gained significantly more weight and consumed significantly more energy than controls, per day of HFD treatment. The increased HFD consumption was matched with a significant increase in hypothalamic fatty acid synthase mRNA. This thesis highlights putative mechanisms by which thyroid hormones affect peripheral metabolism and appetite via the VMN, through interplay with neuronal fatty acid homeostasis.