Thyroid hormone modulates glucose production via a sympathetic pathway from the hypothalamic paraventricular nucleus to the liver.

Abstract

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 (T(3)) administration on EGP. We used stable isotope dilution to measure EGP before and after i.c.v. bolus infusion of T(3) or vehicle in euthyroid rats. To study the role of hypothalamic preautonomic neurons, bilateral T(3) microdialysis in the paraventricular nucleus (PVN) was performed for 2 h. Finally, we combined T(3) microdialysis in the PVN with selective hepatic sympathetic denervation to delineate the involvement of the sympathetic nervous system in the observed metabolic alterations. T(3) microdialysis in the PVN increased EGP by 11 +/- 4% (P = 0.020), while EGP decreased by 5 +/- 8% (ns) in vehicle-treated rats (T(3) vs. Veh, P = 0.030). Plasma glucose increased by 29 +/- 5% (P = 0.0001) after T(3) microdialysis versus 8 +/- 3% in vehicle-treated rats (T(3) vs. Veh, P = 0.003). Similar effects were observed after i.c.v. T(3) administration. Effects of PVN T(3) microdialysis were independent of plasma T(3), insulin, glucagon, and corticosterone. However, selective hepatic sympathectomy completely prevented the effect of T(3) microdialysis on EGP. We conclude that stimulation of T(3)-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.

• Authors: Lars P Klieverik, Sarah F Janssen, Annelieke van Riel, Ewout Foppen, Peter H Bisschop, Mireille J Serlie, Anita Boelen, Mariëtte T Ackermans, Hans P Sauerwein, Eric Fliers, Andries Kalsbeek
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 14 Pg. 5966-71 (Apr 07 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19321430 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Thyroid Hormones
• Triiodothyronine
• Glucose

Topics

• Animals
• Blood Glucose (analysis)
• Glucose (biosynthesis, metabolism)
• Liver (innervation, metabolism)
• Neurons
• Paraventricular Hypothalamic Nucleus (metabolism)
• Rats
• Sympathetic Nervous System (cytology, physiology)
• Thyroid Hormones (physiology)
• Triiodothyronine (administration & dosage, pharmacology)