Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. The aim of our study was to characterize central action of thyroid hormones on energy balance. Here, we demonstrate that either whole body hyperthyroidism or central administration of triiodothyronine (T3) decrease the activity hypothalamic AMP-activated protein kinase (AMPK), resulting in activation of acetyl-CoA carboxylase (ACC) and increased expression of fatty acid synthase (FAS). Such induction of hypothalamic de novo lipogenesis increases activity in the sympathetic nervous system (SNS) and upregulates thermogenic markers in brown adipose tissue (BAT). Pharmacological and genetic manipulation provide evidence that inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Furthermore inhibition of thyroid hormone receptors (TRs) in the VMH reverses the weight loss associated with hyperthyroidism, which underlines the importance of the hypothalamic effects of thyroid hormone in controlling energy balance. This regulatory mechanism depends on AMPK inactivation as genetic ablation of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increased expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockage of the SNS. Overall, these findings demonstrate that thyroid-hormone-induced modulation of AMPK activity and lipid metabolism in the hypothalamus is an important regulator of energy homeostasis. Furthermore, our data indicates that central targeting of AMPK leading to increased activation of BAT thermogenic program may represent a novel therapeutic approach to treat obesity.