The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin

Abstract

Prolonged fasting is associated with a downregulation of the hypothalamo-pituitary thyroid (H-P-T) axis, which is reversed by administration of leptin. The hypothalamic melanocortin system regulates energy balance and mediates a number of central effects of leptin. In this study, we show that hypothalamic melanocortins can stimulate the thyroid axis and that their antagonist, agouti-related peptide (Agrp), can inhibit it. Intracerebroventricular (ICV) administration of Agrp (83-132) decreased plasma thyroid stimulating hormone (TSH) in fed male rats. Intraparaventricular nuclear administration of Agrp (83-132) produced a long-lasting suppression of plasma TSH, and plasma T4. ICV administration of a stable alpha-MSH analogue increased plasma TSH in 24-hour-fasted rats. In vitro, alpha-MSH increased thyrotropin releasing hormone (TRH) release from hypothalamic explants. Agrp (83-132) alone caused no change in TRH release but antagonized the effect of alpha-MSH on TRH release. Leptin increased TRH release from hypothalami harvested from 48-hour-fasted rats. Agrp (83-132) blocked this effect. These data suggest a role for the hypothalamic melanocortin system in the fasting-induced suppression of the H-P-T axis.

Figure 1

The effects of (a) ICV Agrp (83–132) (2 nmol) on plasma TSH in fed rats and (b) ICV NDP-MSH (5 nmol) on plasma TSH in 24-hour–fasted rats. Either peptide or saline was administered to the rat 3rd ventricle in the early light phase (0900–1100 hours). Plasma TSH concentration was measured at 10, 20, and 40 minutes after injection. ^AP < 0.05 versus saline-injected control group.

Figure 2

The effect of iPVN Agrp (83–132) on (a) plasma TSH and (b) plasma T4. Agrp (0.1 nmol) or saline was administered into the rat PVN in the beginning of the dark phase (1900–2000 hours). Plasma TSH and T4 concentrations were measured at the end of the dark phase, 15 hours after injection (0900–1100 hours). Three groups were investigated: saline; (saline injected and ad libitum fed), Agrp (Agrp injected and ad libitum fed), Agrp/FR (Agrp-injected and food-restricted [FR] to saline control group). ^AP < 0.01 versus saline-injected group, ^BP < 0.005 versus saline-injected group.

Figure 3

The effects of α-MSH (100 nM), Agrp (83–132) (100 nM), and both α-MSH (100 nM) and Agrp (83–132) (100 nM) on TRH release from hypothalamic explants harvested from (a) fed animals and (b) 48-hour–fasted animals. ^AP < 0.01 versus basal period.

Figure 4

The effect of leptin (100 nM) on α-MSH release (a, c) and TRH release (b, d) from the hypothalami harvested from fed rats (a, b) and 48-hour–fasted rats (c, d). ^AP < 0.05 versus basal period. ^BP < 0.005 versus saline.

Figure 5

The effect of leptin (100 nM), Agrp (83–132) (100 nM), and both leptin (100 nM) and Agrp (83–132) (100 nM) on TRH release from hypothalami harvested from 48-hour–fasted rats. ^AP < 0.05 versus basal period.

Figure 6

A hypothetical model showing changes of hypothalamic POMC, Agrp, and melanocortin receptor activation in fed animals, fasted animals, and hypothalamic slices. In the fed state, high level of circulating leptin increases POMC and decreases Agrp, resulting in high activation of melanocortin receptor. In this situation, exogenous α-MSH is inactive and Agrp is active. In the fasted state and in the hypothalamic slice, low or no circulating leptin induces changes of the central melanocortin system, low POMC, high Agrp, and low melanocortin receptor activation. In this situation, exogenous α-MSH is active and Agrp is inactive.