Introduction: Childhood obesity is a global health problem that is associated with various metabolic complications, such as insulin resistance, type 2 diabetes, dyslipidemia, and cardiovascular diseases. The mechanisms underlying the development of insulin resistance in childhood obesity are not fully understood. Nephroblastoma overexpressed gene (NOV), also known as CCN3, is a member of the CCN family of matricellular proteins that modulate cell proliferation, differentiation, adhesion, migration, and survival. Previous studies have shown that NOV/CCN3 is involved in glucose metabolism and insulin signaling in various tissues and cell types. However, the role of NOV/CCN3 in childhood obesity and insulin resistance remains unclear. Methods: In this study, we aimed to investigate the association between plasma NOV/CCN3 levels and insulin resistance in 58 obese and 43 non-obese children aged 6–12 years. We measured plasma NOV/CCN3 levels by enzyme-linked immunosorbent assay and assessed insulin resistance by homeostasis model assessment of insulin resistance (HOMA-IR). We also collected clinical and biochemical data, such as body mass index (BMI), waist circumference (WC), blood pressure (BP), fasting glucose (FG), fasting insulin (FI), lipid profile, and inflammatory markers. Results: We found that plasma NOV/CCN3 levels were significantly higher in obese children than in non-obese children (p < 0.001) and positively correlated with BMI (r = 0.42, p < 0.001), WC (r = 0.38, p < 0.001), BP (r = 0.35, p < 0.001), FG (r = 0.31, p < 0.001), FI (r = 0.45, p < 0.001), HOMA-IR (r = 0.48, p < 0.001), triglycerides (r = 0.28, p < 0.001), low-density lipoprotein cholesterol (r = 0.26, p < 0.001), and C-reactive protein (CRP) (r = 0.32, p < 0.001). Multiple linear regression analysis revealed that plasma NOV/CCN3 levels were independently associated with HOMA-IR after adjusting for age, sex, BMI, WC, BP, FG, FI, lipid profile, and CRP (β = 0.36, p < 0.001). Conclusion: These results suggest that plasma NOV/CCN3 levels are elevated in childhood obesity and are associated with insulin resistance, indicating that NOV/CCN3 may play a role in the pathogenesis of metabolic disorders in obese children.

1.
World Health Organization
.
Obesity and overweight
. Available from: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight.
2.
NCD Risk Factor Collaboration NCD-RisC
.
Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults
.
Lancet
.
2017
;
390
(
10113
):
2627
42
. .
3.
Kao
KT
,
Sabin
MA
.
Type 2 diabetes mellitus in children and adolescents
.
Aust Fam Physician
.
2016
;
45
(
6
):
401
6
.
4.
DeFronzo
RA
,
Tripathy
D
.
Skeletal muscle insulin resistance is the primary defect in type 2 diabetes
.
Diabetes Care
.
2009
;
32
(
Suppl 2
):
S157
63
. .
5.
Matthews
DR
,
Hosker
JP
,
Rudenski
AS
,
Naylor
BA
,
Treacher
DF
,
Turner
RC
.
Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man
.
Diabetologia
.
1985
;
28
(
7
):
412
9
. .
6.
Samuel
VT
,
Shulman
GI
.
Mechanisms for insulin resistance: common threads and missing links
.
Cell
.
2012
:
148
(
5
):
852
71
. .
7.
Perbal
B
.
NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issues
.
Mol Pathol
.
2001
;
54
(
2
):
57
79
. .
8.
Chen
CC
,
Lau
LF
.
Functions and mechanisms of action of CCN matricellular proteins
.
Int J Biochem Cell Biol
.
2009
;
41
(
4
):
771
83
. .
9.
Sakamoto
K
,
Yamaguchi
S
,
Ando
R
,
Miyawaki
A
,
Kabasawa
Y
,
Takagi
M
, et al
.
The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway
.
J Biol Chem
.
2002
;
277
(
33
):
29399
405
. .
10.
Lin
CG
,
Chen
CC
,
Leu
SJ
,
Grzeszkiewicz
TM
,
Lau
LF
.
Integrin-dependent functions of the angiogenic inducer NOV (CCN3): implication in wound healing
.
J Biol Chem
.
2005
;
280
(
9
):
8229
37
. .
11.
Joliot
V
,
Martinerie
C
,
Dambrine
G
,
Plassiart
G
,
Brisac
M
,
Crochet
J
, et al
.
Proviral rearrangements and overexpression of a new cellular gene (nov) in myeloblastosis-associated virus type 1-induced nephroblastomas
.
Mol Cell Biol
.
1992
;
12
(
1
):
10
21
. .
12.
Martinerie
C
,
Chevalier
G
,
Rauscher
FJ
3rd
,
Perbal
B
.
Regulation of nov by WT1: a potential role for nov in nephrogenesis
.
Oncogene
.
1996
;
12
(
7
):
1479
92
.
13.
Pakradouni
J
,
Le Goff
W
,
Calmel
C
,
Antoine
B
,
Villard
E
,
Frisdal
E
, et al
.
Plasma NOV/CCN3 levels are closely associated with obesity in patients with metabolic disorders
.
PLoS One
.
2013
;
8
(
6
):
e66788
. .
14.
Martinerie
C
,
Garcia
M
,
Do
TT
,
Antoine
B
,
Moldes
M
,
Dorothee
G
, et al
.
NOV/CCN3: a new adipocytokine involved in obesity-associated insulin resistance
.
Diabetes
.
2016
;
65
(
9
):
2502
15
. .
15.
Paradis
R
,
Lazar
N
,
Antinozzi
P
,
Perbal
B
,
Buteau
J
.
Nov/Ccn3, a novel transcriptional target of FoxO1, impairs pancreatic β-cell function
.
PLoS One
.
2013
;
8
(
5
):
e64957
. .
16.
Isse
FA
,
El-Sherbeni
AA
,
El-Kadi
AOS
.
The multifaceted role of cytochrome P450-Derived arachidonic acid metabolites in diabetes and diabetic cardiomyopathy
.
Drug Metab Rev
.
2022
;
54
(
2
):
141
60
. .
17.
World Health Organization
.
WHO Child Growth Standards: length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: methods and development
.
Geneva
:
World Health Organization
;
2006
.
18.
Martinerie
C
,
Garcia
M
,
Do
TT
,
Antoine
B
,
Moldes
M
,
Dorothee
G
, et al
.
NOV/CCN3: a new adipocytokine involved in obesity-associated insulin resistance
.
Diabetes
.
2016
;
65
(
9
):
2502
15
. .
19.
Fadhil Jaafar
A
,
Afrisham
R
,
Fadaei
R
,
Farrokhi
V
,
Moradi
N
,
Abbasi
A
, et al
.
CCN3/NOV serum levels in coronary artery disease (CAD) patients and its correlation with TNF-α and IL-6
.
BMC Res Notes
.
2023
;
16
(
1
):
306
. Published 2023 Nov 2. .
20.
Waldman
M
,
Singh
SP
,
Shen
HH
,
Alex
R
,
Rezzani
R
,
Favero
G
, et al
.
Silencing the adipocytokine NOV: a novel approach to reversing oxidative stress-induced cardiometabolic dysfunction
.
Cells
.
2022
;
11
(
19
):
3060
. Published 2022 Sep 29. .
21.
Hotamisligil
GS
.
Inflammation and metabolic disorders
.
Nature
.
2006
;
444
(
7121
):
860
7
. .
22.
Gregor
MF
,
Hotamisligil
GS
.
Inflammatory mechanisms in obesity
.
Annu Rev Immunol
.
2011
;
29
:
415
45
. .
23.
Shoelson
SE
,
Lee
J
,
Goldfine
AB
.
Inflammation and insulin resistance
.
J Clin Invest
.
2006
;
116
(
7
):
1793
801
. .
24.
Rosen
ED
,
Spiegelman
BM
.
Adipocytes as regulators of energy balance and glucose homeostasis
.
Nature
.
2006
;
444
(
7121
):
847
53
. .
25.
Saltiel
AR
,
Kahn
CR
.
Insulin signalling and the regulation of glucose and lipid metabolism
.
Nature
.
2001
;
414
(
6865
):
799
806
. .
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