NPY and MC4R signaling regulate thyroid hormone levels during fasting through both central and peripheral pathways

Area of Science:

• Endocrinology
• Neuroscience
• Metabolic regulation

Background:

• Fasting triggers adaptive energy conservation by suppressing the hypothalamic-pituitary-thyroid (HPT) axis.
• Leptin signaling, involving thyrotropin-releasing hormone (TRH) in the paraventricular nucleus (PVN), mediates nutritional status communication to the HPT axis.
• Leptin influences TRH neurons directly or indirectly via arcuate nucleus pathways involving pro-opiomelanocortin (POMC) and agouti-related peptide/neuropeptide Y (AgRP/NPY) neurons.

Purpose of the Study:

• To investigate the in vivo roles of melanocortin 4 receptor (MC4R) and neuropeptide Y (NPY) signaling in the fasting-induced HPT axis suppression.
• To elucidate the specific contributions of MC4R and NPY pathways in central and peripheral regulation of thyroid hormones during fasting.

Main Methods:

• Development of double knockout mice lacking both MC4R and NPY.
• Assessment of Trh expression in the PVN.
• Evaluation of hepatic pathways involved in thyroxine (T4) metabolism during fasting.

Main Results:

• Neuropeptide Y (NPY) is essential for suppressing Trh expression in the PVN during fasting.
• Both MC4R and NPY are required for the activation of hepatic pathways that metabolize T4 in response to fasting.
• These findings highlight the dual role of these pathways in central and peripheral thyroid hormone regulation.

Conclusions:

• NPY signaling is critical for the central suppression of the HPT axis during fasting.
• The combined action of MC4R and NPY mediates peripheral adaptation of thyroid hormone metabolism.
• These pathways are key communicators of fasting signals, leading to reduced thyroid hormone levels.