Irisin and FNDC5 in retrospect: An exercise hormone or a transmembrane receptor?

Abstract

FNDC5 (fibronectin domain-containing [protein] 5) was initially discovered and characterized by two groups in 2002. In 2011 FNDC5 burst into prominence as the parent of irisin, a small protein containing the fibronectin type III domain. Irisin was proposed to be secreted by skeletal muscle cells in response to exercise, and to circulate to fat tissue where it induced a transition to brown fat. Since brown fat results in dissipation of energy, this pathway is of considerable interest for metabolism and obesity. Here I review the original discoveries of FNDC5 and the more recent discovery of irisin. I note in particular three problems in the characterization of irisin: the antibodies used to detect irisin in plasma lack validity; the recombinant protein used to demonstrate activity in cell culture was severely truncated; and the degree of shedding of soluble irisin from the cell surface has not been quantitated. The original discovery proposing that FNDC5 may be a transmembrane receptor may deserve a new look.

Keywords: FNDC5; brown adipocyte; exercise; fibronectin; irisin.

Figure 1. Structure of an FNIII domain, and diagram of FNDC5 sequence showing domains. (A) A ribbon diagram of an FNIII domain from tenascin, from pdb file 1ten, generated with PyMol (http://pymol.org/sites/default/files/pymol_0.xml). All FNIII domains have this same folding structure. (B) The sequence of mouse FNDC5 (NP_081678) showing domains. The FNIII domain is separated into proposed β strands, with the ABE sheet on the bottom and the C’CFG sheet on top.