The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin.
2000

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.

Discussion
In this study, central administration of Agrp (83–132) to rats significantly decreased plasma TSH and total T4, whereas NDP-MSH increased plasma TSH. Consistent with these findings, a-MSH increased TRH release from hypothalamic explants and Agrp (83–132) blocked the a-MSH–induced increase in TRH release.

The hypothalamic melanocortin system has been shown to respond to changes in nutritional status (12, 13). For example, Agrp mRNA increases by 10- to 15-fold after a 48-hour–fast (12), and POMC mRNA has been reported to decrease in response to fasting (25). We have shown here that the effects of exogenous Agrp (83–132) and NDP-MSH on the H-P-T axis are also dependent on feeding status. ICV Agrp (83–132) decreases plasma TSH in the fed state but not in the fasted state, whereas, conversely, NDP-MSH increases plasma TSH in the fasted state but not in the fed state. However, in isolated hypothalamic explants from both fed and fasted animals, TRH release is increased in response to a-MSH, but Agrp (83–132) alone has no effect.

The following model, illustrated in Figure 6, may explain these findings. In the fasted state, circulating leptin is low (4). This decreases hypothalamic POMC (25) and, thus, the melanocortin receptor agonist a-MSH, and increases Agrp (12). Thus, melanocortin receptor activation is likely to be at a low level in the fasted state. Hence, exogenous Agrp had no significant effect, as there was little endogenous melanocortin receptor activation for it to block. When exogenous NDP-MSH was administered to fasted animals, it was able to increase melanocortin receptor activation and to increase plasma TSH.

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In the fed state, circulating leptin is high, POMC is high, and Agrp is low. Hence, melanocortin receptor activation would be at a high level. Under these circumstances, exogenous NDP-MSH was without effect, as melanocortin receptors were already activated, but exogenous Agrp was able to block this receptor activation, and reduced plasma TSH.

PMID: 10749579