Supplementary file 1. Candidate biomarkers tested in this study
Cluster
Name of Molecule
Structure
Main
Tissue(s) of
Origin
Main Target
Tissue(s)
Main Biological Effect(s)
Potential Medical
Application(s) /
Target Diseases
 β cell function regulation
(insulin secretion, glucose
homeostasis) 1
Metabolism
Adipsin or
complement
factor D (CFD)
Encoded by the
CFD gene
Chymotrypsin
family of serine
proteases
 Pre-adipocyte
differentiation 3
Adipose
tissue 1,2
Pancreas (islets  Promotion of glucose
transport for triglyceride
of Langerhans)
1
accumulation in
adipocytes and lipolysis
inhibition 2
 Type 2 diabetes 1
 Obesity 5
 Ischemiareperfusion 6
 Sepsis 7
 Formation of membrane
attack complex 3 through
activation of the
alternative complement 4
Encoded by the
APLN gene
Metabolism
Apelin (APLN)
Endogenous
ligand for the
G-proteincoupled APJ
receptor
Adipose
tissue 8
Heart, lung,
kidney, liver,
brain,
endothelium 9
Vessels, heart,
brain, gastrointestinal tract,
bone
(osteoclasts) 9
 Angiogenesis 10,11
 Hypertension 12
 Hypotensor 12
 Chronic heart
failure 21
 Embryonic heart
8,15,22-25
development: migration of  Obesity
cell progenitors fated to
 Chronic liver
cardiomyocytes 13
disease 26
 Cardiac contractility
stimulator 14,15
 Regulation of water and
food intake at the brain
level 16
 Glucose metabolism
regulation 17 (inhibits
insulin secretion18)
 Muscle glucose uptake 19
 Histamine release and
acid secretion modulation
20
 Adipogenesis
(proliferation and
differentiation) 28,29,36
Encoded by the
RARRES2 gene
Synthesized as
pro-chemerin
Metabolism
Chemerin
Chemoattractant Adipose
protein
tissue 28-30
activated
through serine
protease Cterminal
cleavage 27
Adipose tissue
29
 Glucose homeostasis and
insulin sensitivity 30,37
Immunological  Immune cell migration
cells 31-33
 Angiogenesis 34,39
Endothelium 34  Osteoblastogenesis 36
Muscle 35
 Obesity-associated
complications 27,28
38
 Insulin resistance 37
 Metabolic
syndrome 28,40
 Biomarker of lung
cancer 38
 Myogenesis 35
 Polycystic ovarian
syndrome 41
 Chemotaxis of dendritic
cells and macrophage
enhancement 31
 Inflammatory
bowel disease 42
 Host defence 33
 Inflammatory processes
32,40
Encoded by the
FGF19 gene
Metabolism
Fibroblast growth
factor 19 (FGF19)
Belongs to the
FGF
superfamily,
FGF19
subfamily 43
Brain 43,44
Intestine
Adipose tissue
45
43,45
Liver
45
Fibroblast growth
factor 21 (FGF
21)
Belongs to the
FGF
superfamily,
FGF19
subfamily 43,50
Encoded by the
GHRL gene
Metabolism
Obestatin
It is presumed
to be cleaved
from C-ghrelin
58
 Phosphate and vitamin D
homeostasis modulation 45
 Hepatic glucose and
protein metabolism 46
 Chronic bile acid
malabsorption and
diarrhea 47,48
 Metabolic disorders
46,47,49
 Thermogenic recruitment
of white adipose depots 51
Encoded by the
FGF21 gene
Metabolism
 Bile acid and serum
phosphate homeostasis
regulation 43,45
Liver 43
Adipose tissue
45
 Regulation of fatty acid
oxidation, tricarboxylic
acid cycle flux, and
gluconeogenesis 52
 Brown fat activation 53
 Metabolic diseases
(obesity,
hyperglycemia,
hypertriglyceridemi
a, type 2 diabetes)
54-57
 Glucose uptake in
adipocytes 54
Mainly by
Adipose tissue  Adipocyte function 61
epithelial cells 61
 Protection against dietof the
Gastrointestinal induced insulin resistance
stomach and
tract 62
and inflammation 61
small intestine
59
Pancreas 63
 Anorexigenic 66
 Obesity 67,68
 Type 2 diabetes 6870
 Hypertension 71
 Chronic obstructive
Pancreas,
Brain 64
adipose tissue, Heart 65
muscle, liver,
lung 60
 Glucose and lipid
metabolism regulation 60
 β-cell survival 63
 Anti-inflammation 60
pulmonary disease
72
 Cardiovascular
events 65,73
 Irritable bowel
syndrome 74
 Insulin resistance
and type 2 diabetes
79-81
 Obesity 75,79,80
Metabolism
Omentin
Encoded by the
omentin 1 and
omentin 2 genes
Visceral
adipose tissue
75-77
Visceral tissue
75-77
Endothelium
78
Metabolism
Pigment
epitheliumderived factor
(PEDF)
Encoded by the
SERPINF1 gene
Belongs to the
noninhibitory
serpin family 89
Nervous
system 89
Wide range of
tissues 90,91
Retinal
pigmented
epithelium 92
Endothelium 93
 Insulin sensitivity
modulation 75
 Cardiovascular
disease 79,82-84
 Anti-inflammation 79
 Atherosclerosis 85,86
 Vasorelaxation and
angiogenesis 79
 Hypertension 79,87
 Neurotrophism 89
 Anti-angiogenic and antitumorigenic 90,96-98
 Inflammationrelated diseases
(Crohn´s disease
and rheumatoid
arthritis) 77,88
 Choroidal
neovascularization
91
 Cardiovascular
diseases 91,99
 Cancer 91
Tumor cells
94,95
 Anti-inflammation 102
Metabolism
Zinc-α2glycoprotein
(ZAG)
Encoded by the
ZAG gene
Adipose
tissue 100,101
Adipose tissue
100,104
Liver, breast,
and prostate
102,103
Angiogenesis
Vascular
endothelial
growth factor-A
(VEGF-A)
Encoded by the
VEGFA gene
Wide range of
tissues
(mainly
endothelium)
109,110
)
 Lipid mobilizer and
lipolytic 100,101,105 via
binding to β3adrenoreceptors 106
 Energy expenditure
enhancement 100,101,105
Endothelium
109,110
Nervous
system 111
 Pro-angiogenic and
related processes
(increased vascular
permeability, endothelial
cell growth, cell
migration, and inhibition
of apoptosis) 109,110,112,113
 Monocyte/macrophage
migration 114
 Normoalbuminuric
diabetic
nephropathy 107
 Cancer associated
cachexia 100
 Obesity and type 2
diabetes 105,108
 Excessive
angiogenesisassociated
alterations (cancer,
retinopathy,
choroidal
neovascularization,
arthritis,
atherosclerosis,
psoriasis, and
endometriosis)
115,116
 Insufficient
angiogenesisassociated
alterations (heart,
brain and peripheral
ischemia, type 2
diabetes,
hypertension, preeclampsia, and
nephropathy) 115,116
Encoded by the
FLT1 gene
Angiogenesis
Soluble fms-like
tyrosine kinase-1
(sFlt-1, also
termed ‘soluble
vascular
endothelial factor
receptor-1’
(sVEGFR-1))
Truncated
version of the
cell membranespanning
VEGFR1,
which binds and Placenta 117
then reduces the
Endothelium
circulating
118
levels of
vascular
endothelial
growth factor
(VEGF) and
placental
growth factor
(PlGF) 116
Muscle 119
Endothelium
118
 Anti-angiogenic 116,118
 Excessive
angiogenesisassociated
alterations (cancer,
retinopathy,
choroidal
neovascularization,
arthritis,
atherosclerosis,
psoriasis, and
endometriosis)
115,116
 Insufficient
angiogenesisassociated
alterations (heart,
brain and peripheral
ischemia, type 2
diabetes,
hypertension, preeclampsia, and
nephropathy) 115,116
Encoded by the
AHSG gene
Inflammation
Fetuin-A or α2HS-glycoprotein
Belongs to the
cystatin family
(cysteine
protease
inhibitors)
Prenatal:
brain, liver,
bone, kidney,
respiratory
and
cardiovascular
systems 120
Postnatal:
Liver 121 and
bone
(osteoblast)
 Cardiovascular
events 130 and
atherosclerosis 131
 Gestational diabetes
Secreted into
the
bloodstream
and transported
into the bone
121
 Calcification of different
tissues (vessels, lung
heart, kidneys) 123-126
 Bone homeostasis and
mineralization 127,128
 Insulin receptor function
inhibition 128,129
122
132
 Metabolic disorders
(insulin resistance,
obesity and nonalcoholic fatty liver
disease) 128
 Biomarker in
neurodegenerative
diseases 128
 Biomarker in acute
inflammation and
trauma 128,133
Encoded by the
GRN gene
Inflammation Progranulin
Tumor cells
Granulin
134
precursor
protein whose
Nervous
cleavage
system 135
produces
several products
Adipose tissue
 Cancer 134,137
 Growth factor-like
activities 134
136
 Immunomodulation
Nervous
system 134
 Neurotrophism
 Inflammation 17
134
134
 Pro-inflammation 17
 Macrophage infiltration
 Dementia
(Alzheimer´s
disease and
frontotemporal
lobar degeneration)
into adipose tissue 17
134,138,139
 Multiple sclerosis
140
Bone
formation
Osteocalcin (OC)
or bone gammacarboxyglutamic
acid-containing
protein (BGLAP)
Encoded by the
BGLAP gene
Synthesis is
vitamin K
dependent
Bone
(osteoclast)
Pancreas 141
 Pro-osteoblastic 141
Bone
(osteoclast) 141
 β-cell proliferation and
glucose homeostasis 141-143
Adipose tissue
 Testosterone synthesis
enhancement 144
141
141
 Bone formation 145
and related
alterations such as
osteoporosis 146
 Type 2 diabetes
143,147
 Male fertility 144
 Osteoporosis 153,154
Bone
formation
Osteoprotegerin
(OPG, also
termed
‘osteoclastogenesis
inhibitory factor’)
Encoded by the
TNFRSF11B
gene
Belongs to the
TNF receptor
family
 Bone anti-resorption 148
Wide range of
tissues 148
Bone 148
Vessels 149
 Cancer bone-related
disease 155 such as
osteoarthritis 156
 Vascular
calcification 154
 Modulation of
differentiation and activity
 Cardiovascular
of the osteoblastic and
diseases 149,157
osteoclastic lineage 150-152
 Mental disorders 158
 Metabolic
alterations (type 2
diabetes) 159
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