NPY and MC4R Signaling Regulate Thyroid Hormone Levels during Fasting through Both Central and Peripheral Pathways

SummaryFasting-induced suppression of the hypothalamic-pituitary-thyroid (HPT) axis is an adaptive response to decrease energy expenditure during food deprivation. Previous studies demonstrate that leptin communicates nutritional status to the HPT axis through thyrotropin-releasing hormone (TRH) in the paraventricular nucleus (PVN) of the hypothalamus. Leptin targets TRH neurons either directly or indirectly via the arcuate nucleus through pro-opiomelanocortin (POMC) and agouti-related peptide/neuropeptide Y (AgRP/NPY) neurons. To evaluate the role of these pathways in vivo, we developed double knockout mice that lack both the melanocortin 4 receptor (MC4R) and NPY. We show that NPY is required for fasting-induced suppression of Trh expression in the PVN. However, both MC4R and NPY are required for activation of hepatic pathways that metabolize T4 during the fasting response. Thus, these signaling pathways play a key role in the communication of fasting signals to reduce thyroid hormone levels both centrally and through a peripheral hepatic circuit.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (107 K)Download as PowerPoint slideHighlights▸ Fasted HFD mice are unable to suppress the HPT axis ▸ Npy−/− mice fail to suppress Trh mRNA and TSH during a fast ▸ Fasting mice that lack NPY and MC4R fail to suppress Trh, TSH, and thyroid hormone ▸ MC4R and NPY are required for activation of hepatic metabolism of T4