Thyrotoxicosis increases endogenous glucose production (EGP) and induces hepatic insulin resistance. We have recently shown that these alterations can be modulated by selective hepatic sympathetic and parasympathetic denervation, pointing to neurally mediated effects of thyroid hormone on glucose metabolism. Here, we investigated the effects of central triiodothyronine (T3) administration on EGP. We used stable isotope dilution to measure EGP before and after i.c.v. bolus infusion of T3 or vehicle in euthyroid rats. To study the role of hypothalamic preautonomic neurons, bilateral T3 microdialysis in the paraventricular nucleus (PVN) was performed for 2 h. Finally, we combined T3 microdialysis in the PVN with selective hepatic sympathetic denervation to delineate the involvement of the sympathetic nervous system in the observed metabolic alterations. T3 microdialysis in the PVN increased EGP by 11 ؎ 4% (P ‫؍‬ 0.020), while EGP decreased by 5 ؎ 8% (ns) in vehicle-treated rats (T3 vs. Veh, P ‫؍‬ 0.030). Plasma glucose increased by 29 ؎ 5% (P ‫؍‬ 0.0001) after T3 microdialysis versus 8 ؎ 3% in vehicle-treated rats (T3 vs. Veh, P ‫؍‬ 0.003). Similar effects were observed after i.c.v. T3 administration. Effects of PVN T3 microdialysis were independent of plasma T3, insulin, glucagon, and corticosterone. However, selective hepatic sympathectomy completely prevented the effect of T3 microdialysis on EGP. We conclude 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 represents a unique central pathway for modulation of hepatic glucose metabolism by thyroid hormone.deiodinase ͉ hepatic glucose metabolism ͉ hypothalamus ͉ microdialysis ͉ sympathetic nervous system T hyroid hormones are crucial regulators of metabolism, as illustrated by the profound metabolic derangements in patients with thyrotoxicosis or hypothyroidism (1). Thyrotoxicosis is associated with an increase in endogenous glucose production (EGP), hepatic insulin resistance, and concomitant hyperglycemia (1, 2). We have recently shown that selective hepatic sympathetic denervation attenuates the hyperglycemia and increased EGP during thyrotoxicosis, while selective hepatic parasympathetic denervation aggravates hepatic insulin resistance in thyrotoxic rats. By inference, the increase in EGP during thyrotoxicosis may be mediated in part by sympathetic input to the liver, while parasympathetic hepatic input may function to restrain insulin resistance during thyrotoxicosis (3).The central nervous system is emerging as an important target for several endocrine and humoral factors in regulating metabolism. Hormones like insulin (4), estrogen (5), and corticosteroids (6) appear to use dual mechanisms to affect metabolism: that is, by direct actions in the respective target tissue and by indirect actions via the hypothalamus, in turn affecting target tissues via autonomic nervous system projections. For example, it has been convinci...

OBJECTIVEThe hypothalamic neuropeptide orexin influences (feeding) behavior as well as energy metabolism. Administration of exogenous orexin-A into the brain has been shown to increase both food intake and blood glucose levels. In the present study, we investigated the role of endogenous hypothalamic orexin release in glucose homeostasis in rats.RESEARCH DESIGN AND METHODSWe investigated the effects of the hypothalamic orexin system on basal endogenous glucose production (EGP) as well as on hepatic and peripheral insulin sensitivity by changing orexinergic activity in the hypothalamus combined with hepatic sympathetic or parasympathetic denervation, two-step hyperinsulinemic-euglycemic clamps, immunohistochemistry, and RT-PCR studies.RESULTSHypothalamic disinhibition of neuronal activity by the γ-aminobutyric acid receptor antagonist bicuculline (BIC) increased basal EGP, especially when BIC was administered in the perifornical area where orexin-containing neurons but not melanocortin-concentrating hormone–containing neurons were activated. The increased BIC-induced EGP was largely prevented by intracerebroventricular pretreatment with the orexin-1 receptor antagonist. Intracerebroventricular administration of orexin-A itself caused an increase in plasma glucose and prevented the daytime decrease of EGP. The stimulatory effect of intracerebroventricular orexin-A on EGP was prevented by hepatic sympathetic denervation. Plasma insulin clamped at two or six times the basal levels did not counteract the stimulatory effect of perifornical BIC on EGP, indicating hepatic insulin resistance. RT-PCR showed that stimulation of orexin neurons increased the expression of hepatic glucoregulatory enzymes.CONCLUSIONSHypothalamic orexin plays an important role in EGP, most likely by changing the hypothalamic output to the autonomic nervous system. Disturbance of this pathway may result in unbalanced glucose homeostasis.

Exposure to light at night (LAN) is associated with insomnia in humans. Light provides the main input to the master clock in the hypothalamic suprachiasmatic nucleus (SCN) that coordinates the sleep-wake cycle. We aimed to develop a rodent model for the effects of LAN on sleep. Therefore, we exposed male Wistar rats to either a 12 h light (150–200lux):12 h dark (LD) schedule or a 12 h light (150–200 lux):12 h dim white light (5 lux) (LDim) schedule. LDim acutely decreased the amplitude of daily rhythms of REM and NREM sleep, with a further decrease over the following days. LDim diminished the rhythms of 1) the circadian 16–19 Hz frequency domain within the NREM sleep EEG, and 2) SCN clock gene expression. LDim also induced internal desynchronization in locomotor activity by introducing a free running rhythm with a period of ~25 h next to the entrained 24 h rhythm. LDim did not affect body weight or glucose tolerance. In conclusion, we introduce the first rodent model for disturbed circadian control of sleep due to LAN. We show that internal desynchronization is possible in a 24 h L:D cycle which suggests that a similar desynchronization may explain the association between LAN and human insomnia.