Thyroid hormone modulates glucose production via a sympathetic pathway from the hypothalamic paraventricular nucleus to the liver - PubMed (original) (raw)

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

Lars P Klieverik et al. Proc Natl Acad Sci U S A. 2009.

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

(A) Mean plasma glucose concentration in i.c.v. Veh- and T3-treated animals, before (basal) and after (24 h) bolus i.c.v. infusion. Note the marked, 22% plasma glucose increase in i.c.v. T3-treated rats, whereas in Veh-treated rats there was no significant effect on plasma glucose. ANOVA indicated P = 0.003 for factor time and P = 0.032 for factor time*group. *, P < 0.01. (B) EGP before (Bas) and after (24 h) i.c.v. T3 or Veh bolus infusion. EGP tended to increase after i.c.v. T3- treated rats (*, P = 0.057), but not in i.c.v. Veh-treated animals (P = 0.482). ANOVA indicated P = 0.062 for factor time.

Fig. 2.

(A) Mean plasma glucose concentration in intra-hypothalamic Veh (Veh MD) and T3 MD-treated rats, before (Bas) and after (2 h) MD. Note the pronounced increase of plasma glucose in T3 MD-treated rats, as compared to the mild increase in Veh MD-treated rats. ANOVA indicated P < 0.0001 for factor time and P = 0.005 for factor time*group. *, P < 0.05, **, P < 0.0001. (B) EGP before (Bas) and after (2 h) T3 or Veh MD in the hypothalamic PVN. Note the EGP increase after 2 h of T3 MD, in contrast to the EGP decrease in Veh Md-treated animals, with no difference in basal EGP between groups. ANOVA revealed P = 0.029 for factor time*group. “, P < 0.01, *, P < 0.05.

Fig. 3.

(A) Relative difference between basal plasma glucose and plasma glucose after [Δ Glucose (%)] (i) in i.c.v. Veh- or T3-treated rats, (ii) in rats treated with Veh MD or T3 MD in the hypothalamic PVN, and (iii) hypothalamic T3 MD in selective hepatic sympathectomized (T3 MD HSx) or sham-denervated (T3 MD Sham) rats. Note the significant increase of plasma glucose in i.c.v. T3 and T3 MD-treated rats relative to their respective Veh controls. Hepatic sympathectomy did not abolish the plasma glucose increase upon T3 microdialysis. *P < 0.05 vs. vehicle control group. (B) Relative difference between basal EGP and EGP after [Δ EGP (%)] (i) in i.c.v. Veh- or T3-treated rats, (ii) in rats treated with vehicle (Veh MD) or T3 MD in the hypothalamic PVN, and (iii) hypothalamic T3 MD in selective hepatic sympathectomized (T3 MD HSx) or sham-denervated (T3 MD Sham) rats. Note that the increase of EGP in response to T3 microdialysis relative to Veh-treated rats, replicated by T3 MD in sham-denervated animals, is totally prevented by selective hepatic sympathectomy. *P ≤ 0.05 Veh MD vs. T3 MD and T3 MD Sham vs. T3 MD HSx.

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Thyroid hormone modulates glucose production via a sympathetic pathway from the hypothalamic paraventricular nucleus to the liver - PubMed (original) (raw)