Table 3.

Examples of receptor-independent signal transduction and biological effects on target tissues mediated by exerkines

Exerkine	Non-receptor target	Mechanism of action	Biological effects	Refs
HSP72	JNK protein	Protein- protein interaction (JNK inhibition) and/or inhibition of upstream JNK signaling	↑ insulin sensitivity and glucose tolerance	464,465
HSP70	NF-κB pathway	Reduced expression of NF-κB p65, inhibition of NF-κB signaling	↓ pathological cardiac hypertrophy	254
HSP27	NF-κB pathway	Proteasomal degradation of phosphorylated I-κBα	↓ apoptosis	257,466,467
NO	NO-activated guanylate cyclase	Phospho-protein activation via NO/cGMP/PKG pathway	↑ endothelial function, cardiac protection, neuronal plasticity & expression of proteins involved in angiogenesis	262,468,469
ROS	MAPK pathway, NF-κB pathway	Phosphorylation/dephosphorylation of key players of signaling pathways	↑ skeletal muscle adaption to exercise	266–268
ANGPTL4	Lipoprotein lipase	Inhibition of lipoprotein lipase	Regulation of lipid metabolism in non-exercising vs. exercising muscle	243
	β-adrenergic receptors	Potentiates β-adrenergic signaling via cAMP/PKA	↑ WAT lipolysis	245
FST	Activin A, myostatin	Sequestration of activin A and myostatin	↑ skeletal muscle hypertrophy & insulin signaling	241,242
Decorin	Myostatin	Sequestration of myostatin	↑ skeletal muscle hypertrophy	337
miRNAs	Regulation of gene expression	RNA silencing and post-transcriptional regulation of gene expression	Exercise-induced adaptations	77
Lactate	Hypothalamic neurons	Serves as energy source for leptin-induced phosphorylation of JAK2/STAT3 in hypothalamic neurons	↓ food intake & exercise-induced suppression of appetite	251
	Cellular redox state	Modification of cellular redox state, expression of thermogenic genes	↑ adipose tissue browning	252
GLPD1	Membrane-bound protein release	Hydrolyzation of GPI-anchored proteins	↑ hippocampal neurogenesis and cognitive performance	210
Adropin	NLRP3 inflammasome	Suppression of NLRP3 inflammasome activation	↓ inflammation in NASH	249

All studies listed in this table are animal or in vitro studies

HSP heat shock protein, JNK c-Jun N-terminal kinases, NO nitric oxide, ROS reactive oxygen species, ANGPTL4 angiopoietin-like 4, FST Follistatin, WAT white adipose tissue, miRNA microRNA, GPI glycophosphatidylinositol, GPLD1 glycophosphatidylinositol-specific phospholipase D1, NLRP3 NOD-, LRR- and pyrin domain-containing protein 3, NASH nonalcoholic steatohepatitis