Agouti-Related Protein (AGRP) Has a Central Inhibitory Action on the Hypothalamic-Pituitary-Thyroid (HPT) Axis; Comparisons between the Effect of AGRP and Neuropeptide Y on Energy Homeostasis and the HPT Axis

Abstract

Because alpha-MSH has a potent stimulatory action on hypophysiotropic TRH synthesizing neurons in the hypothalamic paraventricular nucleus (PVN), preventing the effects of fasting on the gene expression of the TRH prohormone (proTRH), we hypothesized that agouti-related protein (AGRP), a melanocortin receptor antagonist, may exert a central inhibitory action on these neurons. To test the hypothesis, the effects of intracerebroventricularly administered AGRP on circulating thyroid hormone levels and proTRH mRNA in the hypothalamic paraventricular nucleus (PVN) were compared with the effects of the recently described central inhibitor of the HPT axis, neuropeptide Y (NPY). AGRP administration increased food consumption and weight gain, suppressed circulating levels of thyroid hormones (T(3) and T(4)), and resulted in an inappropriately normal TSH. These alterations were associated with a significant suppression of proTRH mRNA in the PVN, indicating that AGRP infusion resulted in a state of central hypothyroidism. While similar observations were made in the NPY-infused animals, AGRP-treated animals had higher feeding efficiency, higher T(4) levels, and lower type 2 iodothyronine deiodinase levels in brown adipose tissue than NPY-infused animals. These data demonstrate that AGRP and NPY have a similarly potent inhibitory action on the proTRH gene expression of hypophysiotropic neurons, indicating that both AGRP and NPY may play a major role in the inhibition of the HPT axis during fasting.

Interactions between the melanocortin system and the hypothalamo–pituitary–thyroid axis

“…However, CNS administration of AgRP did not affect type 2 deiodinase activity in brown adipose tissue (BAT), a major effector organ for thyroid hormones in regulating thermogenesis [20]. This finding, together with a marked reduction in pro-TRH mRNA expression in the PVN, suggests that AgRP acts centrally, via TRH suppression within the PVN, rather than peripherally to reduce circulating thyroid hormones.…”

“…Conversely, CNS infusion of AgRP to ad libitum fed rats produces central hypothyroidism, with reduced plasma thyroid hormones, inappropriately normal or decreased TSH and suppressed PVN pro-TRH mRNA expression [20,60]. However, CNS administration of AgRP did not affect type 2 deiodinase activity in brown adipose tissue (BAT), a major effector organ for thyroid hormones in regulating thermogenesis [20].…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…This method has been used to define the direct role played by T 3 in the TRH negative feedback mechanism (487,488) and to study the photoperiod-mediated regulation of seasonal energy balance and reproduction in the Siberian hamster (517). Furthermore, the direct role played by a number of neuropeptides on the HPT axis has been studied using the ICV route; for example, aMHS, neuropeptide-Y, and agouti-related protein (518)(519)(520)(521)(522).…”

Differential Adaptations of the Hypothalamus-Pituitary-Thyroid Axis Between Food Restriction and Anorexia

“…Hypothalamic T 3 production, catalyzed by D2, triggers the synthesis of mitochondrial uncoupling protein 2, which is critical for the activation of NPY/AgRP neurons during fasting (Coppola et al, 2007). NPY and AgRP inhibit TRH gene expression on hypophysiotrophic TRH neurons (Fekete et al, 2001(Fekete et al, , 2002, in contrast, CART/α-MSH stimulate TRH gene expression in the PVN, and this effect is enhanced by leptin (Fekete et al, 2000a(Fekete et al, , 2000b; both neuronal populations of ARC express leptin receptors and are inversely regulated by circulating leptin concentrations (Ahima et al, 2000).…”

“…In the PVN, some of the target cells of NPY are those that synthesize TRH that contain NPY-Y1 receptors (Broberger et al, 1999); NPY-Y1 receptors are activated during fasting or food restriction by the increased release of NPY, which in turn inhibits TRH synthesis (Fekete et al, 2001(Fekete et al, , 2002.…”