Secreted Factors: Tissue “Kines”

Last Updated: November 22, 2024

Introduction to Tissue Kines

Numerous tissues produce and secrete substances that act locally or at a distance but that are not defined by the classic definition of a hormone. These substances include metabolites, lipids, and bioactive peptides. These bioactive substances act as signaling molecules and influence systemic metabolism. The term coined to define these substances in “kine” such as in adipokine, myokine, lipokine, etc. Many tissue kines can also be classified as hormones. In most cases the tissue kines are produced and released in response to some stimulus such as dietary composition, stress, or exercise. The descriptions of the various tissue kines included in this page are not intended to be all inclusive but aimed at defining many of the important molecules secreted by various tissues and now classically defined as kines.

Adipose Tissue Hormones and Adipokines

Adipose tissue is not merely an organ designed to passively store excess carbon in the form of fatty acids esterified to glycerol (triglycerides). Mature adipocytes synthesize and secrete numerous enzymes, growth factors, cytokines and hormones that are involved in overall energy homeostasis. Many of the factors that influence adipogenesis are also involved in diverse processes in the body including lipid homeostasis and modulation of inflammatory responses. In addition, a number of proteins secreted by adipocytes play important roles in these same processes. In fact recent evidence has demonstrated that many factors secreted from adipocytes are proinflammatory mediators and these proteins have been termed adipocytokines. Members of this class of protein secreted from adipocytes include TNFα, IL-6 and leptin. Listed in the Table below is only a subset of proteins known to be secreted by adipose tissue and the focus is on those that effect overall metabolic homeostasis and modulate inflammatory processes. As is clear from the Table, not all the proteins are unique to adipose tissue.

Table of Representative Adipose Tissue Hormones and Adipokines

Factor	Principal Source	Major Actions / Comments
adiponectin also called adipocyte complement factor 1q-related protein (ACRP30), and adipoQ	adipocytes	go to Adipose Tissue: Not Just Fat page
adipsin (also called complement factor D)	adipocytes, liver, monocytes, macrophages	rate limiting enzyme in complement activation
apelin	white adipose tissue (WAT), skeletal muscle, vascular stromal cells, heart	name is derived from the fact that the peptide was identified as the ligand for the GPCR referred to as APJ (APJ endogenous ligand; coupling proteins (e.g. UCP1 which is also known as thermogenin); enhances skeletal muscle mass as well as density of mitochondrialevels increase with increased insulin; exerts positive hemodynamic effects; may regulate insulin resistance by facilitating expression of BAT uncoupling proteins (e.g. UCP1, thermogenin)
chemerin	adipocytes, liver	modulates expression of adipocyte genes involved in glucose and lipid homeostasis such as GLUT4 and fatty acid synthase (FAS); potent anti-inflammatory effects on macrophages expressing the chemerin receptor (chemokine-like receptor-1, CMKLR1)
C-reactive protein (CRP)	hepatocytes, adipocytes	is a member of the pentraxin family of calcium-dependent ligand binding proteins; assists complement interaction with foreign and damaged cells; enhances phagocytosis by macrophages; levels of expression regulated by circulating IL-6; modulates endothelial cell functions by inducing expression of various cell adhesion molecules, e.g. ICAM-1, VCAM-1, and selectins; induces MCP-1 expression in endothelium; attenuates NO production by downregulating NOS expression; increases expression and activity of PAI-1
IL-6	adipocytes, hepatocytes, skeletal muscle, activated Th2 cells, and antigen-presenting cells (APCs)	acute phase response, B cell proliferation, thrombopoiesis, synergistic with IL-1 and TNFα on T cells; enhances fatty acid uptake and glucose metabolism in liver and adipose tissue; enhances insulin production by pancreas
leptin	predominantly adipocytes, mammary gland, intestine, muscle, placenta	go to Adipose Tissue: Not Just Fat page
monocyte chemotactic protein-1 (MCP-1)	leukocytes, adipocytes	is a chemokine defined as CCL2 (C-C motif, ligand 2); recruits monocytes, T cells, and dendritic cells to sites of infection and tissue injury
omentin	visceral stromal vascular cells of omental adipose tissue	the omentum is one of the peritoneal folds that connects the stomach to other abdominal tissues, enhances insulin-stimulated glucose transport, levels in the blood inversely correlated with obesity and insulin resistance
plasminogen-activator inhibitor-1 (PAI-1)	adipocytes, monocytes, placenta, platelets, endometrium	go to the Hemostasis: Biochemistry of Blood Coagulation page
resistin	adipocytes, spleen, monocytes, macrophages, lung, kidney, bone marrow, placenta	go to Adipose Tissue: Not Just Fat page
TNFα	primarily activated macrophages, adipocytes	induces expression of other autocrine growth factors, increases cellular responsiveness to growth factors and induces signaling pathways that lead to proliferation
vaspin	visceral and subcutaneous adipose tissue	is a serine protease inhibitor, levels decrease with worsening diabetes, increase with obesity and impaired insulin sensitivity
visfatin; also called pre-B cell colony-enhancing factor (PBEF); these two independent activities are identical to the enzyme nicotinamide phosphoribosyltransferase (NAMPT)	ubiquitously expressed with highest levels of expression in visceral white adipose tissue	was originally reported to have insulin mimetic effects but that paper was subsequently retracted; the intracellular version of NAMPT (sometimes referred to as iNAMPT) has nicotinamide phosphoribosyltransferase activity; the extracellular version (eNAMPT) exhibits cytokine-like activity; conflicting results relative to insulin receptor binding but blocking insulin receptor signaling interferes with effects of eNAMPT; changes in NAMPT activity occur during fasting and positively regulate the activity of the NAD+-dependent deacetylase, SIRT1, leading to alterations in gene expression

Lipokines: Bioactive Lipid Derivatives

Lipokine is the term coined to describe bioactive lipid molecules that function as endocrine factors. Although the major tissue source for the lipokines is white and brown adipose tissue (WAT and BAT) many other tissues produce and secrete these lipid mediators. Lipokines are derived from various fatty acids that includes essential fatty acids and fatty acid acquired in the diet. Greater detail on a wide array of bioactive lipids, many of which are classified as lipokines, is covered in the Bioactive Lipids and Lipid Sensing Receptors page.

The biological activity of lipokines is most often mediated by enzymes that produce and degrade individual mediators. Minor changes in chemical structure of a given lipokine can dramatically change the activity of the signaling lipid. For example, palmitic acid, which is a 16-carbon saturated fatty acid (C16:0), exerts a mild suppressive effect on insulin-mediated phosphorylation of AKT/PKB, whereas the monounsaturated fatty acid (MUFA) counterpart, palmitoleic acid (C16:1) has no suppressive effect on AKT/PKB phosphorylation and actually stimulates glucose uptake. Similarly, lipokines derived from an arachidonate backbone activate mitochondrial thermogenesis, whereas arachidonic acid itself suppresses mitochondrial activity.

Many lipokines are formed by the addition of fatty acid chains to other molecules, such as amino acids, predominantly glycine, or even fatty acids themselves via acylation reactions. For example, some of the N-acylglycinamides are secreted in response to cold exposure and act as mitochondrial uncouplers in a broad variety of different cell types. Similarly, the metabolic effects of branched fatty acid esters of hydroxy fatty acids (FAHFA) include improvement in glucose tolerance and increase glucose stimulated insulin secretion.

Table of Representative Lipokines

Factor(s)	Lipid Source	Major Actions / Comments
12-hydroxyeicosapentaenoic acid (12-HEPE)	eicosapentaenoic acid, EPA (C20:5)	produced from EPA via actions of 12-LOX; induces glucose uptake following the activation of an as yet unidentified Gs-type G-protein-coupled receptor (GPCR) that, when activated, stimulates the mobilization of GLUT4 transporters to the plasma membrane
12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME)	linoleic acid (C18:2)	produced from linoleic acid via actions of CYP2J or CYP2C subfamily enzymes which generate the epoxy fatty acids, 9,10-epoxyoctadecenoic acid (9,10-EpOME) and 12,13-EpOME; the epoxy-fatty acids are then hydrolyzed to form 9,10-diHOME and 12,13-diHOME by the action of an epoxide hydrolase, primarily soluble epoxide hydrolase (sEH encoded by the EPHX1 and EPHX2 genes); the actions of the sEH enzymes are strongly induced by exercise and cold exposure; is also referred to as an exerkine; functions as an autocrine factor for BAT; induces skeletal muscle fatty acid uptake
1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol), designated PI[(18:1/18:1)]	oleic acid (C18:1)	a phosphatidylinositol (PI) that contains oleic acid at both the sn1 and sn2 positions; inhibits p38 MAPK activation; counteracts activation of the unfolded protein response (UPR) and apoptosis, as well as regulating activation of autophagy
Anandamide (arachidonoylethanolamine (AEA)	arachidonic acid (C20:4)	activates the cannabinoid receptors (CB1 and CB2); involved in central nervous system (CNS) regulation of feeding behavior via regulation of the expression and/or action of several hypothalamic anorexigenic and orexigenic peptides
Branched-chain fatty acid esters of hydroxy fatty acids (FAHFA)	C-16 or C-18 fatty acid either saturated or monounsaturated (palmitoleic, palmitic, oleic, or stearic acid) linked to a hydroxylated C-16 or C-18 lipid, again either saturated or monounsaturated	three major classes of FAHFA which includes the branched-chain FAHFA whose synthesis was shown to be regulated by both fatty acid content of the diet (e.g. high-fat diets) and by fasting; actions of FAHFA include decreasing blood glucose levels while increasing the levels of the gut and pancreatic hormone GLP-1; also increase insulin secretion
Oleoylethanolamine (OEA)	oleic acid (C18:1)	produced in intestinal enterocytes; is a member of the fatty-acid ethanolamide (N-acylethanolamines, NAE) family that includes palmitoylethanolamide (PEA), N-arachidonoylethanolamine (anandamide), N-docosahexaenoyl ethanolamine (synaptamide), and N-stearoylethanolamine; results in increased secretion of the incretin hormones GLP-1 and GIP; activates anorexigenic responses in the brain via engagement of vagal sensory afferent (to the brain) fibers that converge on the nucleus of the solitary tract (NTS) in the brain stem
N-acylgycinamides	arachidonic, palmitic, oleic, stearic, linoleic, and docosahexenoic acids	identified fatty acyl glycinamides include N-arachidonoylglycine (NAGly), N-palmitoylglycine (PalGly), N-oleoyglycine, (OlGly), N-stearoylglycine (StrGly), N-linoleoylglycine (LinGly), and N-docosahexaenoylglycine (Doc-Gly); research suggests that NAGly functions as a ligand for the orphan GPCR, GPR18 and/or GPR92
Palmitoleic acid	palmitoleic acid (C16:1)	critical monounsaturated fatty acid (MUFA); is an omega-7 MUFA; synthesis increases in response to exercise; is also considered an exerkine; exerts effects in white adipose tissue, liver, skeletal muscle, pancreas, endothelial cells, and immune cells; enhances peripheral insulin sensitivity; increases expression of the insulin receptor and the phosphorylation of insulin receptor substrates (IRS1 and IRS2) and PKB/AKT in liver and muscle; influences vascular function by interfering with pro-inflammatory activation in the vascular system
Prostaglandin E2 (PGE2)	arachidonic acid (C20:4)	series 2 eicosanoid; effects vary depending upon the specific prostaglandin receptor to which it binds (EP1, EP2, EP3, or EP4); binding to the EP3 receptor results in pro-inflammatory effects; binding to the EP4 receptor leads to vasodilation whereas binding to the EP1 receptor results in vasoconstriction; enhancement of platelet aggregation at low physiologic concentration, inhibition at supraphysiologic concentrations

Liver Derived Hepatokines

Hepatocytes produce and secrete hundreds of proteins and peptides. Indeed, a major function of the liver is to produce a multitude of proteins that are found circulating in the vasculature and perform a wide array of functions. The proteins and peptides presented in the following Table are not intended to be a complete assessment of all the hepatocyte derived factors but is a focus on several highly significant proteins that have been shown to exert autocrine, paracrine, and endocrine effects. In particular, the focus is on many of the factors that, when released from the liver, exert global whole body homeostatic processes. The major pathophysiologically significant hepatokines are those that exert regulatory effects on overall lipoid and glucose homeostasis. As might be expected, disruptions in the regulated synthesis and release of these hepatokines contribute to the pathologies of obesity and type 2 diabetes. Many of the hepatokines indicated in the following Table are not unique to the liver but are also expressed and secreted from other tissues as well such as identified adipokines (outlined in the previous Table) and myokines (outlined in the next Table).

Table of Representative Hepatokines

Factor	Principal Source	Major Actions / Comments
angiopoietin-like 3 (ANGPTL3)	hepatocytes	more details in Lipoproteins, Blood Lipids, and Lipoprotein Metabolism page
angiopoietin-like 4 (ANGPTL4)	hepatocytes	more details in Lipoproteins, Blood Lipids, and Lipoprotein Metabolism page
angiopoietin-like 6 (ANGPTL6)	hepatocytes	encoded by the ANGPTL6 gene; originally identified as angiopoietin-related growth factor (AGF); functional ANGPTL6 is associated with lean body mass, protection from obesity, and enhanced insulin sensitivity; conversely reduced levels of ANGPTL6 are correlated with obesity and insulin resistance, accumulation of lipid in the liver and skeletal muscle, and reduced overall energy expenditure
angiopoietin-like 8 (ANGPTL8)	hepatocytes	more details in Lipoproteins, Blood Lipids, and Lipoprotein Metabolism page
C-reactive protein (CRP)	hepatocytes, adipocytes	encoded by the CRP gene; is a member of the pentraxin family of calcium-dependent ligand binding proteins; assists complement interaction with foreign and damaged cells; enhances phagocytosis by macrophages; levels of expression regulated by circulating IL-6; modulates endothelial cell functions by inducing expression of various cell adhesion molecules, e.g. ICAM-1, VCAM-1, and selectins; induces MCP-1 expression in endothelium; attenuates NO production by downregulating NOS expression; increases expression and activity of PAI-1
fetuin A	hepatocytes	protein is derived from the AHSG (α2-Heremans-Schmid glycoprotein) gene; member of the family of liver produced and secreted binding proteins that function as cargo transporters in the blood; (albumin represents archetypal family member); name derived from the fact that levels are most abundant in fetal blood; originally associated with inhibition of vascular calcification; is a naturally occurring inhibitor of insulin receptor tyrosine kinase activity in liver and skeletal muscle; polymorphism in the AHSG gene associated with type 2 diabetes; levels of fetuin A in circulation increase in hepatic steatosis (fatty infiltration of the liver); strongly enhances inflammatory cytokine production in macrophages and adipocytes; inhibits adipocyte production of adiponectin
fetuin B	hepatocytes	encoded by FETUB gene; reduces glucose effectiveness; expression increased in non-alcoholic fatty liver disease (NAFLD); NAFLD is now referred to as metabolic dysfunction-associated fatty liver disease (MAFLD); increased circulating levels associated with type 2 diabetes
FGF21	hepatocytes, adipose tissue, myocytes, pancreas, duodenum	hepatic expression enhanced by glucagon through AMPK and PPARα effects thyroid hormones and glucocorticoids also enhance hepatic FGF21 expression; increases fat utilization and energy expenditure, reduces body weight, reduces whole-body fat mass, reduces lipid content in hepatocytes, improves glucose tolerance, enhances hepatic and peripheral insulin sensitivity; levels of hepatic expression increase in pathologic states such as hepatic steatosis, type 2 diabetes, obesity, and insulin resistance
fibrinogen-like protein 1 (commonly called hepassocin)	hepatocytes	encoded by the FGL1 gene; functions as a hepatocyte growth factor involved in liver regeneration; increased secretion from hepatocytes is associated with insulin resistance and impaired glucose tolerance; enhances the potential for non-alcoholic fatty liver disease (NAFLD) and hepatic steatosis; NAFLD is now referred to as metabolic dysfunction-associated fatty liver disease (MAFLD)
insulin-like growth factor 1 (IGF-1)	hepatocytes provide the vast majority of circulating IGF-1	go to the Growth Factors and Other Cellular Regulators page
leukocyte cell-derived chemotaxin 2 (LECT2)	hepatocytes provide the vast majority of circulating LECT2; other cells express the LECT2 gene such as adipocytes and smooth muscle cells	chemoattractant for neutrophils; regulator of chondrocyte differentiation; levels of LECT2 in circulation are associated with obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD); NAFLD is now referred to as metabolic dysfunction-associated fatty liver disease (MAFLD)
selenoprotein P (SELPP)	hepatocytes	encoded by the SELENOP gene; major selenium transport protein; increased circulating levels associated with insulin resistance; expression reduced in response to insulin; expression elevated by glucose and fatty acids (primarily palmitate); elevated serum selenoprotein P associated with insulin resistance and vascular inflammation; levels of selenoprotein P are inversely correlated to those of adiponectin
serum hormone binding globulin (SHBG)	hepatocytes; also brain, uterus, testes, placenta	encoded by the SHBG gene; normally binds androgens and estrogen in plasma; high circulating levels protect from type 2 diabetes development; reduced levels associated with increased risk for cardiovascular disease; levels decline with hepatic steatosis; polymorphisms in SHBG gene associated with insulin resistance and type 2 diabetes

Skeletal Muscle Derived Myokines

Like adipose tissue and the liver, skeletal muscle produces and secretes a number of proteins and peptides that exert autocrine, paracrine, and endocrine effects. These proteins are collectively referred to as myokines. Like adipokines and hepatokines, many of the regulatory proteins secreted from skeletal muscle are also secreted by other tissues such as the liver and adipose tissue.

Table of Representative Myokines

Factor	Principal Source	Major Actions / Comments
β-aminoisobutyric acid (BAIBA)	skeletal muscle	non-protein amino acid; exists in two enantiomeric forms, D-BAIBA and L-BAIBA; D-BAIBA is generated in the cytosol from thymine while L-BAIBA is generated from valine; has been shown to protect from diet-induced obesity in animal models; activates AMPK, PPARα and PPARβ/δ while inhibiting PPARγ; increased release in response to exercise and thus is also considered an exerkine
angiopoietin 1 (ANGPT1)	cardiac myocytes, smooth muscle	promotes muscle growth and homeostasis; prevents insulin resistance
brain derived neurotrophic factor (BDNF)	cardiac myocytes; smooth muscle; various brain regions	increased β-oxidation of fatty acids; increased glucose oxidation; enhances neurogenesis in the brain improving cognition and spatial memory
ciliary neurotrophic factor receptor (CNTFR)	cardiac myocytes, smooth muscle	functions as a muscle paracrine factor stimulating innervation cell differentiation, and overall muscle homeostasis
decorin	smooth muscle cells, fibroblasts, and stressed vascular endothelial cells	is a stromal proteoglycan that is a member of the small leucine-rich proteoglycan (SLRP) gene family of 18 proteins that are divided into five discrete classes; exhibits high affinity for collagen fibers; has a role in the sequestration of numerous growth factors and the antogonism of several growth factor receptors
FGF21	hepatocytes, adipose tissue, myocytes, pancreas, duodenum	increases fat utilization and energy expenditure, reduces body weight, reduces whole-body fat mass, reduces lipid content in hepatocytes, improves glucose tolerance, enhances hepatic and peripheral insulin sensitivity
follistatin-like protein 1 (FSTL1)	cardiac myocytes, smooth muscle, adipocytes	exerts cardioprotective effects
irisin	skeletal muscle	derived from the FNDC5 encoded membrane-associated protein; stimulates peripheral tissue energy homeostasis, particularly in adipose tissue; details of irisin synthesis and function are covered in the Peptide Hormones and Their Receptors page
IL-6	adipocytes, hepatocytes, skeletal muscle, activated Th2 cells, and antigen-presenting cells (APCs)	enhances fatty acid uptake and glucose metabolism in liver and adipose tissue; enhances insulin production by pancreas
IL-15	monocytes, thyroid, lymph nodes, myocytes	enhances muscle hypertrophy; enhances fatty acid β-oxidation and thermogenesis in brown adipose tissue (BAT)
IL-16	T cells, mast cells, eosinophils, fibroblasts, myocytes	stimulates expression and production of pro-inflammatory cytokines by monocytes
IL-18	macrophages, dendritic cells, lymphocytes, myocytes, and numerous other cell types	synthesized as an inactive precursor that is activated by caspase-1 cleavage; mediates inflammatory processes through the activation of the potent inflammatory gene activating transcription factor, NF-κB (nuclear factor kappa-B), via IL-18 receptor signaling
insulin-like growth factor 1 (IGF-1)	hepatocytes provide the vast majority of circulating IGF-1; myocytes produce locally acting IGF-1	go to the Growth Factors and Other Cellular Regulators page
irisin	skeletal muscle	go to the Peptide Hormones and their Receptors page
musclin	skeletal muscle, brain, bone	is encoded by the osteocrin (OSTN) gene; highly related to natriuretic peptides; expression of the OSTN gene stimulated by insulin; production and secretion stimulated by exercise to promote exercise tolerance via enhanced oxidative phosphorylation; exhibits cardioprotective effects; modulates cardiovascular functions such as blood pressure
myonectin (erythroferrone)	skeletal muscle, erythroblasts	protein identified as a nutrient-responsive metabolic regulator secreted by skeletal muscle and was subsequently shown to be identical to erythroferrone (encoded by the ERFE gene), a hormone produced by erythroblasts; erythroferrone inhibits the production of hepcidin in the liver and so increases the amount of iron available for hemoglobin synthesis; is a member of the the C1q/TNF-related protein (CTRP) family; functions as a nutrient responsive regulator of total body fatty acid metabolism; enhances liver and adipose tissue fatty acid uptake and glucose metabolism
myostatin	skeletal muscle	encoded by the MSTN gene; was originally identified as growth differentiation factor 8 (GDF8); is a member of the TGFβ superfamily; enhances glucose and fatty acid oxidation in skeletal muscle; involved in muscle growth and overall homeostasis; stimulates bone formation and maintenance
vascular endothelial growth factor A (VEGFA)	myocytes; numerous other cell types	initial member of the VEGF family identified; VEGF family consists of five members including VEGFA, VEGFB, VEGFC, VEGFD, and placental growth factor (PIGF); major factor involved in angiogenesis, vasculogenesis and endothelial cell growth; induces endothelial cell proliferation; promotes cell migration; inhibits apoptosis and induces permeabilization of blood vessels; enhances fatty acid and glucose oxidation in skeletal muscle; promotes myocyte differentiation; enhances vasodilation promoting fuel delivery to muscle

Exerkines: Exercise-Induced Kines

The term exerkine was given to any of the signaling molecules that could be identified as being released to the blood in response to acute and/or chronic exercise. These molecules can include bioactive lipids, amino acids, peptides, and proteins. Many molecules defined as exerkines have also been defines as myokines, adipokines, and lipokines. Exerkines exert their effects through endocrine, autocrine, and/or paracrine pathways. Numerous studies have shown that exerkines are involved in many processes including, but not limited to, cardiovascular, metabolic, immune, and neurological homeostasis.

Table of Representative Exerkines