Table 1.
Functions of hepatokines on adipose tissue and clinical application.
| Hepatokine | Full name | Source of hepatokine | Transcriptional regulation | Receptors or ligands | Functions on adipose tissue | Serum concentration in metabolic disorder | Clinical use in metabolic disorder (https://www.clinicaltrials.gov/) | references |
|---|---|---|---|---|---|---|---|---|
| FGF21 | Fibroblast growth factor 21 | Mainly liver, pancreas, brain, adipose tissue | PPARγ, PPARα and ChREBP | FGF receptor 1c/β-klotho complex | WAT: glucose uptake↑; lipolysis↑/↓, adiponectin↑ and WAT browning↑ | Humans with obesity, T2DM↑ HFD feed mice, ob/ob, db/db mice↑ |
Diagnostic and prognostic biomarker treatment (FGF21 analog): LY2405319, Pegbelfermin (BMS-986036), AKR-001 GLP-1-Fc-FGF21 dual antibody; B1344; and PF-05231023 |
22,24,42,46,47,49,55,57,61, 62, 63,188, 189, 190, 191, 192 |
| BAT: energy expenditure and fat utilization↑, thermogenic genes (e g., UCP1) ↑ | ||||||||
| ANGPTL3 | Angiopoietin-like protein 3 | Mainly liver | liver X receptor | lipoprotein lipase (LPL) | WAT: LPL activity↓, lipolysis↑, FFA uptake↑ thereby decreasing DNL and glucose uptake↓ | Humans with obesity, coronary artery disease ↑ | Treatment: Evinacumab (antibody of ANGPTL3); Vupanorsen (an N-acetyl galactosamine-conjugated antisense oligonucleotide drug to ANGPTL3 mRNA) | 43,107,109,110,114,119,122, 123, 124,193 |
| ANGPTL4 | Angiopoietin-like protein 4 | Liver, adipose tissue | PPARs and HIF1α | lipoprotein lipase (LPL) | WAT: LPL activity↓ | Humans with obesity, NAFLD ↑ | Treatment: REGN1001 (ANGPTL4-neutralizing fully human monoclonal antibody) | 193, 194, 195, 196, 197 |
| ANGPTL6 | Angiopoietin-like protein 6 | Mainly liver, adipose tissue | BAT and WAT: stimulates energy expenditure↑, PGC-1 and UCP1 ↑ | Humans with diabtes, obesity↑ | 198, 199, 200 | |||
| FetA | Fetuin-A | Mainly liver, adipose tissue | NF-κB | Toll-like receptor 4 (TLR4) | WAT: subclinical inflammation ↑; macrophage migration and polarization of macrophages↑; adiponectin↓ | Humans with obesity, T2DM↑ | Diagnostic biomarker | 126, 127, 128,131,201,202 |
| Adropin | Adropin | Liver, brain | liver X receptor α | G protein-coupled receptor, GPR19 | WAT: fat accumulation↓, adiponectin↑, lipogenesis↓; proliferation↑; differentiation↓; adipose inflammation↓ | Humans with obesity, T2DM, NAFLD↓ Mice feed a NASH diet↓ |
Diagnostic and prognostic biomarker | 64,66,67,69,71,73,203, 204, 205 |
| FST | Follistatin | Mainly liver | FOXO1 | Transforming growth factor-β (TGF-β) superfamily, such as activin A, myostatin, and bone morphogenetic proteins (BMPs) | WAT: Akt phosphorylation and glucose uptake↓; insulin sensitivity↓ | Humans with T2DM↑ | 132, 133, 134,206 | |
| Activin E | Activin E | Mainly liver | C/EBP | Activin receptor type-1 and type-2 (ACVR1 and ACVR2) | WAT: fat mass↑/↓, WAT browning↑ and UCP1 and FGF21↑ | 99, 100, 101,103, 104, 105 | ||
| BAT: energy expenditure↑ | ||||||||
| TSK | Tsukushi | Mainly liver | BMP4/7, FGF8b, TGF-β and Frizzled | WAT: adipocytes size↑, genes associated with macrophages and adipose inflammation↑ | Mice feed a HFD, NASH diet, MCD diet, db/db mice↑ | 15,136,138,139 | ||
| BAT: energy expenditure↓ | ||||||||
| GPNMB | Glycoprotein nonmetastatic melanoma protein B | Osteoblasts, melanoma, liver, adipose tissue | SREBP | integrin α5β1, CD44 and Na+/K+-ATPase | WAT: adipocytes size↑, lipogenesis↑, WAT browning BAT: UCP1↓, energy expenditure↓ |
Humans with obesity, NAFLD↑ HFD feed mice, ob/ob mice↑ |
142, 143, 144, 145, 146, 147 | |
| Manf | Mesencephalic astrocyte-derived neurotrophic factor | Liver, brain | Neuroplastin | WAT: adipocytes size↓, lipolysis↑, WAT browning, inflammation↓, insulin sensitivity↑ | Humans with T1DM, T2DM↑ HFD feed mice, ob/ob mice↑ |
77, 78, 79,81 | ||
| FNDC4 | Fibronectin type III domain containing 4 | Liver, brain | G-protein coupled receptor 116 (GPR116) | WAT: inflammation↓, insulin sensitivity↑ | Humans with obesity↓ HFD fed mice ↑ |
86,88,89 | ||
| ORM | Orosomucoid | Mainly liver, also adipocytes, heart, and brain | CCR5 and Siglect-5 | WAT: adipogenesis↓ | Humans with T1DM ↑ HFD feed mice, db/db mice↑ |
94, 93, 92, 91 | ||
| LECT2 | Leukocyte cell-derived chemotaxin 2 | Mainly liver | Toll-Like Receptor 3 | tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (Tie1) | 3T3L1: P38 phosphorylation↑; inflammation markers↑; insulin signaling↓; lipid accumulation↑ | Humans with obesity, T2DM, NAFLD ↑ | 212, 211, 210, 209, 208, 207 | |
| RBP4 | Retinol-binding protein-4 | Mainly liver, also adipose tissue | stimulated by retinoic acid-6 (STRA6) and RBP4 receptor-2 (RBPR2) | WAT: antigen-presenting cells↑; macrophage and CD4 T-cell ↑, and adipose tissue inflammation↑, and may increases mobilization of FFAs from adipocytes↑ | Humans with obesity, T2DM↑ | Prognostic biomarker | 218, 217, 216, 215, 214, 213 | |
| DPP4 | Dipeptidyl-peptidase 4 | Liver, adipose tissue and Intestinal | NF-κB, HIF1α | caveolin-1 (Cav1) and proteinase-activated receptor 2 (PAR2) | WAT: fat mass↑; adipose tissue inflammation↑; and impair insulin pathway↓ | Humans with obesity, T2DM, NAFLD↑ | Treatment (DPP4 inhibitor): linagliptin; saxagliptin; DBPR108; alogliptin and anagliptin |
176,187,224, 223, 222, 221, 220, 219 |
| BAT: PPAR-α, PGC-1, and UCP1↓ | ||||||||
| Selenoprotein P, SHBG, Hepassocin: mainly expressed and secreted by the liver, also play significant roles in glucose and lipid metabolism, but there are little studies demonstrate their functions in adipose tissue. | 160,230, 229, 228, 227, 226, 225 | |||||||