Pre-autonomic neurons in the hypothalamic paraventricular nucleus (PVN) project to sympathetic and parasympathetic motor nuclei in the brain stem, from where the liver and white adipose tissue (WAT) are innervated by both branches of the autonomic nervous system (ANS). Studies by our group and by others have shown that these neural pathways modulate glucose and lipid metabolism in liver and WAT. Given the abundant thyroid hormone receptor (TR) expression in the PVN we hypothesized that thyroid hormone modulates hepatic glucose metabolism via the ANS. Moderate thyrotoxicosis increased endogenous glucose production (EGP) as measured by stable isotope dilution, while inducing hepatic insulin resistance. Selective hepatic sympathectomy partly prevented these effects. Bilateral T3 microdialysis in the PVN of euthyroid rats increased plasma glucose and EGP independently of serum T3 and corticosterone. In addition, selective hepatic sympathectomy completely prevented the stimulating effect of hypothalamic T3 administration on EGP. These experiments demonstrate that stimulation of T3-sensitive neurons in the PVN of euthyroid rats increases EGP via sympathetic projections to the liver, independently of circulating glucoregulatory hormones. This novel route may explain in part the beneficial effects of beta-adrenergic blockers in patients with severe thyrotoxicosis. As estrogen (E2) and corticosterone are additional endocrine determinants of glucose metabolism and in view of the abundant estrogen and glucocorticoid receptor expression in the PVN, we currently investigate if similar neural routes exist for metabolic effects of estrogen and corticosterone. In addition, we aim to unravel the hypothalamic pathways that transmit the actions of these hormones onto the autonomic nervous system, focusing on pituitary adenyl cyclase-activating polypeptide (PACAP), TRH and orexin. These studies add a new dimension to the complex metabolic actions of classical hormones and may help to uncover a role for the brain in the pathogenesis of the metabolic syndrome.