Fc (human):FNDC4 (rec.)

Irisin is a recently described exercise-induced hormone secreted by skeletal muscle in mice and humans. Irisin activates beige fat cells (beige cells have a gene expression pattern distinct from either white or brown fat and are preferentially sensitive to the polypeptide hormone irisin). Irisin is cleaved from the type I membrane protein FNDC5 and improves systemic metabolism by increasing energy expenditure. FNDC4 is an ortholog of FNDC5 with 50% identity and 86% similarity compared to Irisin. FNDC4 as well as FNDC5 are extremely well conserved between species. The human FNDC4 gene is highly enriched in liver, brain tissue and adipocytes. FNDC4 is a factor with direct therapeutic potential in inflammatory bowel disease and possibly other inflammatory diseases. Recently, a new role of FNDC4 as a hepatokine has been published. Liver primarily controls the circulating levels of FNDC4 showing tight correlation with insulin sensitivity. In addition, a new orphan adhesion G protein-coupled receptor 116 (GPR116) has been identified as a receptor of FNDC4 in white adipose tissue (WAT), thereby establishing an endocrine FNDC4-GPR116 axis in the control of systemic glucose homeostasis. Moreover, the FNDC4-GPR116 axis is impaired in diabetic patients and therapeutic injections of recombinant Fc-FNDC4 into pre-diabetic mice corrected pre-diabetic hyperglycemia. Protein function: Acts as an anti-inflammatory factor in the intestine and colon. Binds to and acts on macrophages to downregulate pro- inflammatory gene expression. Affects key macrophage functions, including phagocytosis, by downregulating many key pathways for macrophage activation, partly via by STAT3 activation and signaling. May be required to dampen the immunological response in colitis. [The UniProt Consortium]