TABLE 1

Batokines and their known functions

BatokineClassEndogenous Tissue(s)Confirmed StimulationFunction(s)References
AdenosineNucleoside—β-adrenergic stimulationActivates thermogenesis in BAT; induces beiging in WAT; reduces obesity in mice(Lee, Lee, and Oh 2019; Gnad et al., 2014)
AdiponectinProtein hormoneBAT, WATCold exposurePromotes WAT beiging(Ahmad et al., 2021; Hui et al., 2015)
Angiopoietin-Like8 (ANGPTL8)Or LipasinProteinBAT, WAT, liverCold exposureNot fully elucidated, but assumed to negatively regulate BAT thermogenesis(Lee, Lee, and Oh 2019; Fu et al., 2013)
BMP8-bProteinBAT, hypothalamus—Regulates thermogenesis, promotes sympathetic innervation of adipose tissue via NRG-4, enhances lipolysis via HSL(Ahmad et al., 2021; Pellegrinelli et al., 2018; Whittle et al., 2012)
CXCL14CytokineBATCold exposurePromotes WAT beiging, alternatively activated M2 macrophage recruitment(Ahmad et al., 2021; Cereijo et al., 2018)
Endothelin 121-amino acid peptideBAT, beige adipocytes, vascular endothelial cells, brainGq signaling, inhibited by β-adrenergic stimulationSuppresses UCP1 expression, beige and brown adipogenesis and whole-body energy expenditure(Ahmad et al., 2021; Klepac et al., 2016; Lee, Lee, and Oh 2019)
EPDR1ProteinBAT, WAT—Thermogenic (beige/brown) adipocyte differentiation; β-adrenergic signal response, important in BAT mitochondrial respiration and whole body metabolism(Ahmad et al., 2021; Deshmukh et al., 2019)
FGF21ProteinBAT, liver, skeletal muscle, heartCold exposure, β-adrenergic stimulation, BAT TxProtection against hypertension, cardiac hypertrophy and MI injury. Promotes WAT beiging, increases thermogenic function in BAT, and reduces dyslipidemia and insulin resistance in T2D patients(Ahmad et al., 2021; Stanford et al., 2013; Lee et al., 2014; Ruan et al., 2018; Planavila et al., 2013; Liu et al., 2013; Hondares et al., 2011; Wang, Tao, et al., 2015; Gaich et al., 2013; Villarroya et al., 2017b)
Follistatin (Fst)GlycoproteinBAT, nearly all tissuesCold exposureInhibits TGF-β/Smad3/myostatin signaling and therefore promotes BAT function and improves lipid homeostasis and whole body metabolism.(Lee, Lee, and Oh 2019; Singh, Braga, and Pervin 2014)
GDF-15CytokineBAT, liver, kidney, heart, and lungCold exposure, β-adrenergic (requires FGF21)Targets macrophages; anti-inflammatory(Ahmad et al., 2021; Campderros et al., 2019)
IL-6InterleukinBAT, heart, smooth muscle, skeletal muscleBAT Tx, β-adrenergicPromotes glucose uptake into BAT, WAT, and heart; promotes adipocyte browning; cardioprotection against MI injury; promotes alternative M2 macrophage activation(Ahmad et al., 2021; Stanford et al., 2013; Kristof et al., 2019; Burysek and Houstek 1997; Villarroya et al., 2017b; Mauer et al., 2014)
IGF1Protein hormoneBAT, liverCold exposure, BAT TxPromotes β-cell function, protects against cytotoxicity and insulitis, anti-inflammatory; anti-diabetic(Ahmad et al., 2021; Gunawardana and Piston 2012, 2015; Duchamp et al., 1997; Villarroya et al., 2017b)
IGFBP-2ProteinBeige adipocytes—Enhances the differentiation of osteoclasts and increases bone density(Ahmad et al., 2021; Rahman et al., 2013; DeMambro et al., 2012; Kawai et al., 2011)
METRNLCytokineBeige adipocytes, mucosal tissues, skinCold exposurePromotes activation of eosinophils, recruits alternatively activated M2 macrophages in WAT(Ahmad et al., 2021; Rao et al., 2014)
MyostatinCytokineBAT, skeletal muscle, heartActivation of Agouti-related peptide neurons (by an energy deficit) promotes the expression of GFP8 in BAT which activates myostatinImpairs skeletal muscle function, insulin stimulated glucose uptake, and brown adipocyte differentiation(Ahmad et al., 2021; Kong et al., 2018; Steculorum et al., 2016; Fournier et al., 2012; Kim et al., 2012; Lee, Lee, and Oh 2019)
Neuregulin 4 (NRG-4)ProteinBAT, liverCold exposureEnhances WAT beiging, represses hepatic lipogenesis, protects against obesity, insulin resistance, and hepatic steatosis(Ahmad et al., 2021; Rosell et al., 2014; Wang et al., 2014; Christian 2014; Villarroya 2017b; Chen et al., 2017)
NGFProteinBATCold exposureIncreases sympathetic innervation and promotes neurite outgrowth(Ahmad et al., 2021; Néchad et al., 1994; Zeng et al., 2019)
Retinol binding protein 4 (RBP4)ProteinBAT, WAT, liverCold exposure, β3-adrenergic stimulationInvolved in the transport of vitamin A derivatives(Villarroya et al., 2017b)
SLIT2-CGlycoprotein (extracellular matrix protein)Beige adipocytes—Stimulates thermogenesis and improves glucose homeostasis; promotes WAT beiging(Ahmad et al., 2021; Kang et al., 2017; Svensson et al., 2016; Lee, Lee, and Oh 2019)
Triiodothyronine (T3)Protein hormoneBATCold exposure, β3-adrenergic stimulation (stimulates thyroxin deiodinase type II, the enzyme which converts thyroxin into the active form of Triiodothyronine)Required for adaptive thermogenesis in BAT; several systemic effects including control of metabolism, cardiac and digestive functions, brain development, and bone maintenance(Ahmad et al., 2021; de Jesus et al., 2001; Silva and Larsen 1985; Villarroya et al., 2017b)
12-HEPEOxylipinBATCold exposure, β3-adrenergic stimulationPromotes glucose uptake into BAT and skeletal muscle(Leiria et al., 2019).
12,13-diHOMEOxylipinBAT, liverCold, exercise, BAT TxPromotes fatty acid uptake into BAT skeletal muscle, and cardiomyocytes, increases CM function and LV hemodynamics(Lynes et al., 2017; Stanford et al., 2018; Pinckard et al., 2021)