Figure 6. Model of NPY and MC4R signaling in T₄ regulation during fasting.

A. During fasting, reduced leptin levels invoke an increase in Npy expression in the arcuate nucleus. NPY signals through Y1 and Y5 receptors in the PVN to repress Trh expression. Central repression of Trh leads to a decrease in Tshβ mRNA levels in the pituitary and thus, reduced T₄ and T₃ levels from the thyroid. Trh and serum TSH levels remain unchanged in fasting Npy^−/− mice, yet T₄ and T₃ levels are decreased. Adapted from (Vella and Hollenberg, 2009), Copyright 2009, The Endocrine Society. B, Npy^−/− mice are able to suppress TH levels during fasting through Nr1i3-mediated hepatic metabolism of TH, which requires both MC4R and NPY. The MC4R and NPY may act on the liver directly, through sympathetic outputs or a combination of both. The Nr1i3-targets SULT1A1, SULT2A1, SULT1D1 and UGT1A1 inactivate TH through sulfation (T₄S) or glucuronidation (T₄G). These genes are regulated during fasting in Npy^−/− mice, but not in DKO mice. T₄S is converted to reverse T₃ sulfate (rT₃S) by the type 1 deiodinase (Dio1) and T₄G is cleared through biliary excretion. 3V = third ventricle. AgRP = agouti-related peptide. α-MSH = α-melanocyte stimulating hormone. Nr1i3 = constitutive androstane receptor. CNS = central nervous system. Dio1 = type 1 deiodinase. MC4R = melanocortin 4 receptor. Ob-Rb = leptin receptor, long form. NPY = neuropeptide Y. POMC = proopiomelanocortin. PVN = paraventricular nucleus. Sults = sulfotransferases. T₃ = triiodothyronine. rT₃S = reverse triiodothyronine sulfate. T₄ = thyroxine. T₄G = glucuronidated thyroxine. T₄S = thyroxine sulfate. TSH = thyroid-stimulating hormone. Trh = thyrotropin-releasing hormone. Ugt1a1 = UDP-glucuronosyltransferase 1A1. Y1, Y5 = NPY receptors.