Irisin, two years later

Abstract

In January 2012, Boström and colleagues identified a new muscle tissue secreted peptide, which they named irisin, to highlight its role as a messenger that comes from skeletal muscle to other parts of the body. Irisin is a cleaved and secreted fragment of FNDC5 (also known as FRCP2 and PeP), a member of fibronectin type III repeat containing gene family. Major interest in this protein arose because of its great therapeutic potential in diabetes and perhaps also therapy for obesity. Here we review the most important aspects of irisin's action and discuss its involvement in energy and metabolic homeostasis and whether the beneficial effects of exercise in these disease states could be mediated by this protein. In addition the effects of irisin at the central nervous system (CNS) are highlighted. It is concluded that although current and upcoming research on irisin is very promising it is still necessary to deepen in several aspects in order to clarify its full potential as a meaningful drug target in human disease states.

Figure 1

Expression of FNDC5 (fibronectin type III domain containing 5), also known as FRCP2 and PeP, is stimulated in muscle by PGC1-α in response to exercise. It is a signal peptide with two fibronectin domains in its amino (N)-terminal part and a hydrophobic domain inserted in the lipidic bilayer at carboxy (C)-terminal domain. The first 29 aa of the mouse FNDC5 are a signal peptide, followed immediately by the single FNIII domain of 94 aa. The next 28 aa are of unknown structure and function and contain the putative cleavage site for irisin. This is followed by a 19 aa transmembrane domain and a 39 aa cytoplasmic domain. FNDC5 is thus a type I transmembrane protein with its FNIII domain extracellular, similar to some cytokine receptors. This structure is synthesized as a type I membrane protein and followed by proteolytic cleavage realising amino (N)-terminal part of the protein into the extracellular to circulation.

Figure 2

Skeletal muscle releases to circulation several hormones denomined myokines acting as endocrine organ. Thus during exercise PGC1α is activated inducing FNDC5 release which is cleaved to irisin. Irisin can act on different tissues, thereby brown adipose tissue activates UCP1 in mitochondria triggering transport protons chain in the mitochondrial membrane, resulting ATP increased and dissipating energy in form of heat. This process increases energy expenditure, reduces body weight, and improves metabolic parameters such as insulin sensitivity. Irisin on white adipose tissue stimulates BAT-like phenotypes changes, increasing PGC1α expression and thereby UCP1 and oxygen consumption while decreases WAT genes, process in which WAT stops behaving as energy reservoir for to use fat as energy source as in BAT, process named browning. For all of this, irisin has been proposed as a possible novel treatment in diabetes and obesity. Other target of irisin is nervous system where preliminary studies suggest that it could act on adipocyte metabolism through a novel neural pathway and on the other hand irisin induces neural proliferation and adequate neural differentiation, so it could also be a therapeutic target for neurodegenerative diseases such as Alzheimer or Parkinson.