Torpor: The Rise and Fall of 3-Monoiodothyronamine from Brain to Gut-From Gut to Brain?

Abstract

3-Monoiodothyronamine (T1AM), first isolated from rat brain, is reported to be an endogenous, rapidly acting metabolite of thyroxine. One of its numerous effects is the induction of a "torpor-like" state in experimental animals. A critical analysis of T1AM, to serve as an endogenous cryogen, is given. The proposed biosynthetic pathway for formation of T1AM, which includes deiodinases and ornithine decarboxylase in the upper intestinum, is an unusual one. To reach the brain via systemic circulation, enterohepatic recycling and passage through the liver may occur. The possible role of gut microbiota is discussed. T1AM concentrations in human serum, measured by a specific monoclonal assay are up to three orders of magnitude higher compared to values obtained by MS/MS technology. The difference is explained by the presence of a high-affinity binder for T1AM (Apolipoprotein B-100) in serum, which permits the immunoassay to measure the total concentration of the analyte but limits MS/MS technology to detect only the unbound (free) analyte, a view, which is contested here.

Keywords: T1AM; apolipoprotein B-100; hibernation; immunoassay; mass spectrometry; monoiodothyronamine; thyroxine; torpor.

Figure 1

The cartoon illustrates important findings in T1AM research as a puzzle: (1) T1AM was isolated first from rat brain and later shown to be present in liver and other rodent tissues. Surprisingly, there are no quantitative data available reporting T1AM contents in other mammalian tissues. (2) The thyroid secretes T₄ and T₃ but human thyroid tissue does not contain T1AM. (3) Rodents cannot convert externally administered T₄, labeled with ¹³C or 13C and ¹⁵N, into T1AM but T₄ is converted by mouse jejunal tissue into T1AM. The enzyme responsible for decarboxylation from deiodinated T₄ intermediates is ornithine decarboxylase (ODC). (4) Apolipoprotein B-100 in LDL is speculated to transport T1AM to target tissues and suggested to interfere with the correct determination of T1AM human serum concentrations with MS/MS but not with immunoassays [Image adapted from Kumar et al. (98)]. (5) The role of the gut microbiota in the biosynthesis of T1AM is unclear but speculated to be of importance.