Obesity Research & Clinical Practice

Hypoadiponectinemia in obese adolescents: the impact on lipid profile and the

incidence of insulin resistance
--Manuscript Draft--

Manuscript Number: ORCP-D-23-00395

Article Type: Research Paper

Keywords: Adiponectin; HOMA IR; Metabolic syndrome; hypo HDL-c

Corresponding Author: Nur Aisiyah Widjaja, Ph.D.

Airlangga University Faculty of Medicine
Surabaya, East Java INDONESIA

First Author: Nur Aisiyah Widjaja, Ph.D

Order of Authors: Nur Aisiyah Widjaja, Ph.D

Roedi Irawan, Ph.D

Meta Herdiana Hanindita, Ph.D

Eva Ardianah

Manuscript Region of Origin: Asia Pacific

Abstract: Purpose: To investigate the impact of hypoadiponectinemia on lipid profile and the
incidence of insulin resistance in obese adolescents.
Methods: A cross-sectional study was conducted from October 2019 until January
2020 involving obese adolescents aged 13-18 years old in Junior and Senior High
Schools student in Surabaya and Sidoarjo. Independent sample T-test or Mann-
Whitney U test, Fischer exact test, and Phi correlation were conducted with a
significant value of P <0.05.
Results: hypoadiponectinemia subjects had lower levels of HDL-c, but had higher
triglyceride levels than subjects with normal adiponectin levels (P<0.05), while other
parameters (LDL-c, total cholesterol, fasting blood glucose, fasting insulin, and blood
pressure) did not differ significantly between two groups. Hypoadiponectinemia was
correlated with the incidence of MetS, hypo HDL-c, and hypertriglyceridemia in obese
adolescents. There was no significant difference in HOMA IR values or the incidence of
IR between hypoadiponectinemia and those with normal adiponectin levels.
Conclusions: Hypoadiponectinemia affects the lipid profile, especially by lowering HDL-
c levels, and stimulates lipolysis so that triglyceride levels are higher in obese
adolescents.

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Cover Letter

August, 8th 2023

Dear Editor of Obesity Research & Clinical Practice

I wish to submit an original research article entitled “Hypoadiponectinemia in obese

adolescents: the impact on lipid profile and the Incidence of insulin resistance” to be
considered for publication by Obesity Research & Clinical Practice,
I confirm that this work is original and has not been published elsewhere, nor is it currently under
consideration for publication elsewhere.
In this paper, we found that HDL-c was lower in hypoadiponectinemia, while triglyceride was
significantly higher. This is significant because adiponectin influences plasma lipoprotein by
altering the expression and activity of the key enzyme responsible for the catabolism of
triglyceride-rich lipoproteins. Hypoadiponectinemia also increase the incidence of
hypertriglyceridemia and hypo HDL-c significantly. While with insulin resistance (IR), we found
no correlation with hypoadiponectinemia, for this phenomenon, it was stated that
hypoadiponectinemia is the result of obesity and IR (due to adipose tissue) and associated
metabolic alterations. Also in the adolescent population, IR is the main determinant of adiponectin
levels more than BMI.
I believe that this manuscript is appropriate for publication by Obesity Research & Clinical
Practice because it focused in adolescents’ health issue and preventing non-communicable disease
in adulthood. Adiponectin had a crucial role in the pathogenesis of atherosclerosis and
cardiovascular diseases associated with obesity and the metabolic syndrome.

Thank you for your consideration of this manuscript.

Sincerely,

Nur Aisiyah Widjaja

Department of Child Health, Faculty of Medicine, University of Airlangga

e-mail: nuril08@yahoo.com
Highlights

STROBE Statement—Checklist of items that should be included in reports of cross-sectional studies

Item Page
No Recommendation No
Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the 1, line 11
title or the abstract
(b) Provide in the abstract an informative and balanced summary of 1, line 15-
what was done and what was found 21
Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation 1, line 37-
being reported 2, line 72
Objectives 3 State specific objectives, including any prespecified hypotheses 2, line 7-
72
Methods
Study design 4 Present key elements of study design early in the paper 3, line 75
Setting 5 Describe the setting, locations, and relevant dates, including periods 3, line 75-
of recruitment, exposure, follow-up, and data collection 85
Participants 6 (a) Give the eligibility criteria, and the sources and methods of
selection of participants
Variables 7 Clearly define all outcomes, exposures, predictors, potential 3, line 90-
confounders, and effect modifiers. Give diagnostic criteria, if 123
applicable
Data sources/ 8* For each variable of interest, give sources of data and details of 3, line 90-
measurement methods of assessment (measurement). Describe comparability of 123
assessment methods if there is more than one group
Bias 9 Describe any efforts to address potential sources of bias -
Study size 10 Explain how the study size was arrived at 3, line 86-
89
Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If 3, line 90-
applicable, describe which groupings were chosen and why 91
Statistical methods 12 (a) Describe all statistical methods, including those used to control 4, line
for confounding 124-131
(b) Describe any methods used to examine subgroups and 4, line
interactions 124-131
(c) Explain how missing data were addressed 4, line
124-131
(d) If applicable, describe analytical methods taking account of 4, line
sampling strategy 124-131
(e) Describe any sensitivity analyses 4, line 30-
31
Results
Participants 13* (a) Report numbers of individuals at each stage of study—eg 5, line
numbers potentially eligible, examined for eligibility, confirmed 134-137
eligible, included in the study, completing follow-up, and analysed
(b) Give reasons for non-participation at each stage 5, line
134-137
(c) Consider use of a flow diagram Figure 1

1
 Descriptive data 14* (a) Give characteristics of study participants (eg demographic, 5, line
clinical, social) and information on exposures and potential 138-145
confounders
(b) Indicate number of participants with missing data for each 5, line
variable of interest 134-137
Outcome data 15* Report numbers of outcome events or summary measures Table 1.
Main results 16 (a) Give unadjusted estimates and, if applicable, confounder- Table 1
adjusted estimates and their precision (eg, 95% confidence interval). 5, line
Make clear which confounders were adjusted for and why they were 139-146
included
(b) Report category boundaries when continuous variables were Table 1
categorized 5, line
139-146
(c) If relevant, consider translating estimates of relative risk into Table 1
absolute risk for a meaningful time period 5, line
139-146
Other analyses 17 Report other analyses done—eg analyses of subgroups and Table 2
interactions, and sensitivity analyses 5, line
147-152
Discussion
Key results 18 Summarise key results with reference to study objectives 5, line 155
– 8, line
235
Limitations 19 Discuss limitations of the study, taking into account sources of 5, line 236
potential bias or imprecision. Discuss both direction and magnitude - 239
of any potential bias
Interpretation 20 Give a cautious overall interpretation of results considering 5, line 155
objectives, limitations, multiplicity of analyses, results from similar – 8, line
studies, and other relevant evidence 239
Generalisability 21 Discuss the generalisability (external validity) of the study results 5, line 155
– 8, line
235
Other information
Funding 22 Give the source of funding and the role of the funders for the present 8, line 247
study and, if applicable, for the original study on which the present
article is based

*Give information separately for exposed and unexposed groups.

Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and
published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely
available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at
http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is
available at www.strobe-statement.org.

2
Title Page (with Author Details)

ORIGINAL RESEARCH ARTICLE

Hypoadiponectinemia in Obese Adolescents: the Impact on Lipid Profile and the

Incidence of Insulin Resistance

Nur Aisiyah Widjaja 1, Roedi Irawan 1, Meta Herdiana Hanindita 1, Eva Ardianah2
1
Department of Child Health, Airlangga University, Surabaya, Indonesia
2
Magister Program, Department of Public Health, Airlangga University, Surabaya, Indonesia

Corresponding Author:
Nur Aisiyah Widjaja, MD
Child Health Department, Faculty of Medicine Univesity of Airlangga
Jl. Mayjen Prof. Dr. Moestopo no. 47
Surabaya, 60132, Indonesia
Phone: +62 812-3073-379
E-mail: nuril08@yahoo.com

Number of Tables: 2

Number of Figures: 0

Word count: 2,828

Keywords: High calorie formula, IGF-1, nutritional intervention, TLC, undernutrition.

Ethics Committee

The study was approved (the number 251/EC/KEPK/FKUA/2019) and declared to be ethically
appropriate by the research health ethic committee Universitas Airlangga, School of Medicine
on October 16th, 2019.

“I have read and have abided by the statement of ethical standards for manuscripts submitted
to the Obesity Research & Clinical Practice”

Conflict of Interest

The authors state no conflict of interest.

Funding Sources

None

Author Contribution

Conceived and Design: Nur Aisiyah Widjaja, Eva Ardianah

Performed the experiments: Eva Ardianah, Meta Herdiana Hanindita

analyzed and interpreted the data: Eva Ardianah, Roedi Irawan

contributed reagents, materials, analysis tools or data: Nur Aisiyah Widjaja, Eva Ardianah,

Meta Herdiana Hanindita, Roedi Irawan

wrote the paper: Nur Aisiyah Widjaja, Eva Ardianah

Manuscript File Click here to view linked References

1 ORIGINAL RESEARCH ARTICLE

2
3 Hypoadiponectinemia in obese adolescents: the impact on lipid profile and the incidence
4 of insulin resistance
5
6
7
8 Abstract
9 Purpose: To investigate the impact of hypoadiponectinemia on lipid profile and the incidence
10 of insulin resistance in obese adolescents.
11 Methods: A cross-sectional study was conducted from October 2019 until January 2020
12 involving obese adolescents aged 13-18 years old in Junior and Senior High Schools student
13 in Surabaya and Sidoarjo. Independent sample T-test or Mann-Whitney U test, Fischer exact
14 test, and Phi correlation were conducted with a significant value of P <0.05.
15 Results: hypoadiponectinemia subjects had lower levels of HDL-c, but had higher triglyceride
16 levels than subjects with normal adiponectin levels (P<0.05), while other parameters (LDL-c,
17 total cholesterol, fasting blood glucose, fasting insulin, and blood pressure) did not differ
18 significantly between two groups. Hypoadiponectinemia was correlated with the incidence of
19 MetS, hypo HDL-c, and hypertriglyceridemia in obese adolescents. There was no significant
20 difference in HOMA IR values or the incidence of IR between hypoadiponectinemia and
21 those with normal adiponectin levels.
22 Conclusions: Hypoadiponectinemia affects the lipid profile, especially by lowering HDL-c
23 levels, and stimulates lipolysis so that triglyceride levels are higher in obese adolescents.
24 Key words: Adiponectin, HOMA IR, Metabolic syndrome, hypo HDL-c
25
26
27 Highlights:
28 1. Adiponectin is significantly lower in obese adolescents with syndrome metabolic
29 (MetS) than non-MetS.
30 2. Low adiponectin levels leading to a condition of hypoadiponectinemia, and the
31 evidence is still scarce.
32 3. Obesity, insulin resistance (IR) and hypoadiponectinemia forming a complicated
33 correlation.
34 4. Hypoadiponectinemia is more frequent in male than female obese adolescents.
35
36 1. Introduction
37 Obesity is linked with hyperinsulinemia and insulin resistance (IR), which leads to metabolic
38 alterations, termed metabolic syndrome (MetS), with clinical manifestations of hypertension,
39 dyslipidemia, and hyperglycemia [1]. The underlying mechanism by which obesity triggers
40 metabolic syndrome remains unclear, but there is a hypothesis that obesity is a low-grade
41 systemic inflammation in adipose tissue, and that macrophages accumulate in this tissue,
42 resulting in the secretion of several adipokines and pro-inflammatory cytokines (TNF-α and
 2

43 IL-6). This alters the insulin signaling pathways, leading on insulin resistance [2]. Moreover,
44 adipose tissue itself is the largest endocrine organ that actively produces several hormones
45 such as leptin, resistin, visfatin, apelin, and adiponectin. With the except of adiponectin, these
46 hormones are positively correlated with obesity [3]. Adipokines have various biological
47 functions, including glucose and lipid metabolism, the control of metabolic stress and
48 maintain vascular wall integrity [4]. Adiponectin is one of the adipokines exclusively secreted
49 by adipose tissue. The level is decreased in obesity, cardiovascular disease, or type 2 diabetes.
50 It is known to be associated with the incidence of metabolic syndrome, and insulin resistance
51 [5]. Adiponectin gene expression and the circulating levels of adiponectin have been
52 correlated with adiposity [6].

53 Obesity is characterized by increased lipid storage in adipose tissue [3], resulting in the
54 enlargement of adipose tissue. This enlargement stimulates the secretion of acute-phase serum
55 amyloid A (SAA). In response to this metabolic alteration, basal lipolysis also increases and
56 leads to the elevation of free fatty acids (FFA) in the circulation system as autocrine feedback
57 [7]. Due to this lipolysis, the incidence of dyslipidemia is also increased in obesity. Obesity
58 also triggers hyperglycemia due to insulin resistance which is caused by many factors
59 (hormones, cytokines, oxidative stress, adipose tissue hypoxia, lipodystrophy, lipotoxicity,
60 etc) [8]. Adiponectin is known to be the regulator of glucose, lipid metabolism, and insulin
61 sensitization, and is the only of adipokines with anti-atherogenic and anti-inflammatory
62 properties, and can bind with matrix proteins (collagen I, III, and V, laminin, fibronectin) and
63 inhibit the formation of initial atherosclerosis lesions by decreasing the expression of
64 adhesion molecules in endothelial cells due to pro-inflammation stimuli. In lipid metabolism,
65 adiponectin suppresses lipid accumulation (enhances lipid β-oxidation) and modulates blood
66 pressure regulation [4].

67 Hypoadiponectinemia is a condition in which there are low levels of adiponectin in the

68 circulation [9]. It has been claimed to be an independent risk factor for hypertension, type 2
69 diabetes mellitus, and myocardial infarction [10], and is linked with IR [1], particularly with
70 abdominal obesity. Hypoadiponectinemia, defined as plasma adiponectin levels < 4 µg/mL,
71 increases the risk of coronary heart disease and metabolic risk factors [11]. Here we study the
72 impact of hypoadiponectinemia on lipid profile and the incidence of IR in obese adolescents.

73
74 2. Methods
 3

75 A cross-sectional study was conducted from October 2019 until January 2020, involving
76 obese adolescents aged 13-18 years old in Junior and Senior High School student in Surabaya
77 and Sidoarjo. Subjects who had consumed corticosteroids in the 6 months before the study,
78 taken dyslipidemia drugs in the 3 months before the study or who were suffering from
79 infections or immune/endocrine disorders were exclude. Inclusion criteria were no antibiotic
80 use, no smoking, no hormonal therapy, and no consumption of alcohol or drugs. which affect
81 body composition. Obesity was determined based on body mass index (BMI) for age based on
82 gender > percentile 95th of centers for disease control (CDC) growth chart 2000. Before the
83 study was conducted, the researchers described the importance of this study to the subject's’
84 parents with the permission of schools’ headteachers. Participation in the study was voluntary
85 and only allowed when the parents had signed an informed consent. Sample sized was
86 calculated:
2
(𝑍1−𝛼⁄ + 𝑍1−𝛽 )
2
87 𝑛=[ ] +3
[(1 + 𝑟)〗
½ ln 〖 1 − 𝑟 ]

(1.96 + 0.84) 2
88 𝑛= +3
1 + 0.35
½ ln[ ]
1 − 0.35

89 The formula designed the total sample (n) was 62  2 groups = 2n = 124. The subjects were
90 selected with consecutive sampling, and then divided into 2 groups: those with
91 hypoadiponectin and those with normal level of adiponectin.

92 2.1 Anthropometry measurements

93 When measuring anthropometry, the subjects had to wear light clothes and no footwear (socks
94 and shoes), belt, hat, or other accessories, including a watch. Female students with a ponytail
95 had to undothe ponytail prior to measuring their height. Anthropometry measurements were
96 collected as follows:

97 1. Body weight was measured using a Seca Robusta 318 digital scale. The subjects were
98 asked to stand upright on the scale. Their body weight appeared on the screen and was
99 noted on the data collection sheet.
100 2. Body height was measured with a Seca 213 stadiometer. The subjects were asked to
101 stand upright on the stadiometer base, with the heel, buttock, and shoulder blades
102 touching the scale pool, their chin up, look straight ahead. The head slider was
 4

103 lowered until it touched the cranium. The body height was noted on the data collection
104 sheet.
105 3. Waist circumference was measured using a Seca 201 measuring tape, by wrapping the
106 measuring tape around the subject's stomach, at the midpoint between the lowest rib
107 and the endpoint of the iliac crest upon expiration, in line with the navel.
108 4. Hip circumference was measured using a Seca 201 measuring tape. The subjects were
109 asked to keep their feet together, then the measuring tape was wrapped around the
110 widest part of the hips, at the point of the greatest gluteal protuberance.

111 2.2 Blood sample

112 Blood samples (5 ml) were withdrawn via vena cubitus, placed in an EDTA-containing tube
113 and transported to the laboratory in an icebox. for profile lipid, fasting blood glucose, insulin,
114 and adiponectin investigation by an experience nurse. Lipid profiles, fasting blood glucose,
115 adiponectin, and insulin levels were measured.

116 2.3 Determination of insulin resistance

117 To determine the subjects with IR and non-IR, HOMA-IR was calculated using the formula:
118 [glucose (mg/dL) x Insulin (µu/L)] / 405. The cut-off value to describe IR was > 3.43 for both
119 sexes, and is appropriate for the paediatric population aged 1 month to 18 years old [12].

120 2.4 Determination of hypoadiponectinemia

121 Hypoadiponectinemia is diagnosed if the levels of adiponectin are <8.3 µg/ml for male, and
122 8.1 µg/ml for female adolescents [13]. This cut-off point is determined based on the
123 possibility of MetS due to the subjects being obese.

124 2.5 Statistical analysis

125 The subjects were divided into two groups based on the presence of hypoadiponectinemia,
126 namely a hypoadiponectinemia and normal adiponectin level group. A test of normality and
127 Levene’s test of homogeneity were conducted to determine the most appropriate further
128 analysis: an independent sample T-test or Mann-Whitney U test and Fischer exact test. The
129 correlation of hypoadiponectinemia with MetS, hypertriglyceridemia, hypertension,
130 hyperglycemia, and hypo HDL-c was analyzed with Phi correlation, with a significant value
131 of p <0.05.

132
133 3. Results
 5

134 A total of 268 subjects with obesity was recruited, but almost half of the subjects were
135 exclude due to had breakfast before went to school (38 subjects) and not completed the blood
136 investigation (100 subjects). Only 130 students with obesity were included the study, and
137 divided into two groups: hypoadiponectinemia and normal adiponectin levels. The subjects’
138 characteristics are summarized in Table 1. Hypoadiponectinemia was predominant (87.69%)
139 in adolescents less than 16 years old (<192 months old), and more prevalent in males
140 (63.08%). There was no significant difference in age distribution, gender distribution,
141 anthropometric measurements, fasting blood glucose, fasting insulin, HOMA IR, or blood
142 pressure between groups. The lipid profile showed no significant difference in total
143 cholesterol or low density lipoprotein-cholesterol (LDL-c) levels, but high density
144 lipoprotein-cholesterol (HDL-c) was significantly lower in hypoadiponectinemia subjects,
145 while triglyceride were significantly higher in hypoadiponectinemia subjects.

146 The Phi correlation between hypoadiponectinemia and MetS and MetS risk factors is shown
147 in Table 2, illustrating that hypoadiponectinemia was weakly correlated with MetS incidence
148 (r=0.186, p=0.034), being higher than in the normal group (53% vs. 35.38%). Central obesity,
149 hypertension, and hyperglycemia were not correlated with hypoadiponectinemia, but were
150 correlated with hypo HDL-c (r=0.287, p=0.001) and hypertriglyceridemia (r=0.216, p=0.014),
151 since their incidence was more prevalent than normal subjects.
152
153 4. Discussion
154 In this study more male than female adolescents tended to have hypoadiponectinemia, which
155 was supported by the findings that females had higher adiponectin than boys. Androgens tend
156 to inhibit the secretion of adiponectin, while estrogens tend to stimulate the synthesis of
157 adiponectin [14]. Another reason for this difference could be the difference in fat distribution
158 between males and females. Body fat distribution is associated with hypoadiponectinemia,
159 particularly with visceral adipose tissue or abdominal obesity, accompanied by
160 hypertriglyceridemia and hypo HDL-c [15]. Another study also found that boys had fat
161 deposits in the central body, while girls in the gynoid area [16]. Visceral fat distribution alters
162 lipid metabolism [15]. Adiponectin level varies along with sex, race, adiposity, and puberty.
163 Prepubertal boys (11-12 years old) had higher adiponectin levels than post-pubertal (16-17
164 years old) in a non-lean obese adolescents' population [17], which contrasts with the result of
165 the current study, in which subjects below 192 months old (>16 years old) had a lower level
166 of adiponectin or were more likely to have hypoadiponectinemia than subjects above 192
 6

167 years old (57 vs. 8 subjects resepctively). A study in the US showed that adiponectin tends to
168 decline in late puberty, but only in males, with lower levels seen in adulthood. When
169 considering ethnicity, adiponectin reached the highest level in adulthood in non hispanic
170 females, whereas hispanic females had lower adiponectin in late puberty and adulthood [18].
171 However another study noted that the effect of puberty on adiponectin levels was only seen in
172 lean subjects, and not obese adolescents [17], which meant that only obese adolescents
173 experienced an alteration in adiponectin secretion [19]. The effect of other aspects such as
174 lifestyle (e.g. smoking exposure) on adiponectin levels should also be considered [20].

175 Our study also revealed that subjects with hypoadiponectinemia had lower levels of HDL-c
176 than did those with normal adiponectin levels, which is consistent with other findings in men.
177 It was found that subjects with hypoadiponectinemia had a significantly lower level of HDL-c
178 [20, 21]. Adiponectin is correlated with lipoprotein metabolism, especially HDL-c and
179 triglycerides, as it increases ATP-binding cassette transporter A1 and lipoprotein lipase (LPL)
180 but decreases hepatic lipase, which then stimulates HDL-c secretion [22].
181 Hypoadiponectinemia also increased triglyceride levels in this study, which is consistent with
182 other studies, that hypoadiponectinemia was not only correlated with higher levels of
183 triglycerides [21], but also other parameters: fasting blood glucose, fasting insulin, and
184 HOMA-IR [21]. However, studies investigating the effect of hypoadiponectinemia on the
185 lipid profile are scarce, particularly in obese adolescents.

186 Adiponectin influences plasma lipoprotein by altering the expression and activity of the key
187 enzyme responsible for the catabolism of triglyceride-rich lipoproteins [1]. Adiponectin in the
188 circulation system is related to the lipid metabolism, which is negatively correlated with
189 triglycerides and LDL-c but positively correlated with HDL-c [23]. This is consistent with
190 another study, in which subjects with hypoadiponectinemia had higher levels of triglyceride,
191 but lower levels of HDL-c than normal subjects. This finding is also consistent with the
192 suggestion that adiponectin correlated with lipoprotein metabolism, especially HDL-c and
193 triglyceride levels. Adiponectin induces HDL-c via several possible pathways: 1) by
194 increasing the hepatic production of apo-AI (the major apolipoprotein HDL-c); 2) by
195 activating the nuclear receptors liver X receptor α and PPARγ, which increases the expression
196 of ATP-binding cassette transporter A1 (ABCA1); 3). by down-regulating hepatic lipase (HL)
197 activity; 4) by activating lipoprotein lipase (LPL); and 5). improvement of insulin resistance.
198 The last one is also able to reduce triglycerides [24].
 7

199 The effect of hypoadiponectinemia in obesity may be increase the ability of TNFα to blocking
200 the action of insulin, thus inducing IR [1]. However, this conflicts with the notion that,
201 hypoadiponectinemia is the result of obesity and IR, and associated with metabolic alterations
202 [11]; our study are consistent with the second suggestion, as there was no significant
203 difference in the incidence of IR and HOMA IR values between those with
204 hypoadiponectinemia and the normal group. This finding is also consistent with other studies,
205 that found no significant difference in fasting glucose, insulin (OGTT), and insulin sensitivity
206 (ISI-composite) among adiponectin groups (low level, medium level, and high level) [25]. A
207 study conducted in adults showed similar results, with no significant difference in HOMA IR
208 values [21]. The metabolic alterations due to hypoadiponectinemia increased the incidence of
209 MetS. Several studies have reported that adiponectin levels were correlated with MetS risk
210 factors (abdominal obesity, hypertriglyceridemia, hypertension, low-level HDL-c, and
211 hyperglycemia) in diabetic patients [26]. A study in the paediatric population showed that
212 adiponectin was correlated with MetS risk factors, except with blood pressure, and that
213 adiponectin was correlated with the presence of MetS [27]. In the adolescent population, IR is
214 the main determinant of adiponectin levels, more than BMI [15]. However, the study which
215 investigae the correlation between hypoadiponectinemia and the incidence of MetS, low
216 levels of HDL-c, and hypertriglyceridemia in paediatric population was limited until now. A
217 study conducted in renal transplantation patients found that hypoadiponectinemia (serum
218 adiponectin range 7.4 to 14.5 µg/ml) was correlated with the incidence of MetS (65%,
219 p=0.008) [28]. In a healthy adult population, hypoadiponectinemia (serum adiponectin level
220 <4.0 µg/ml) increased the incidence of MetS in men (52.3% vs. 11.6%, p<0.001) and women
221 (37.5% vs. 11.4%, p<0.01) [29], which is consistent with our findings.

222 A study in Japanese adults showed that men with hypoadiponectinemia (adiponectin level
223 <4.0 µg/ml) had a higher incidence hypertriglyceridemia (60.6%, p<0.001) and low levels of
224 HDL-c (35.8%, p<0.001) than those with normal adiponectin level. In women,
225 hypoadiponectinemia tended to increase the incidence of hypertriglyceridemia by 37.5%
226 (p<0.05), and of low levels of HDL-c by 18.8% (p<0.05), in comparison with those with
227 normal adiponectin [29], which is consistent with our findings. Hypertriglyceridemia is
228 affected by obesity due to IR. IR increases the activity and expression of hormone-sensitive
229 lipase (HSL) in adipose tissue, which catalyzes the breakdown of triglycerides into FFA. FFA
230 then enters the liver, leading to an increase in very low-density lipoprotein (VLDL)
231 triglycerides and apolipoprotein CIII (apoCIII) [30]. Adiponectin reduces triglyceride levels
 8

232 by enhancing triglyceride catabolism and fatty acid uptake in skeletal muscle and activating
233 the AMPK, p38MAPK, and PPARα signaling pathways, which further activates fatty acid
234 oxidation [6]. In hypoadiponectinemia, those processes did not take place. A limitation of the
235 current study is that it did not investigate the effect of hypoadiponectinemia on atherogenic
236 markers such as soluble adhesion molecule, iNOS ands pro-inflammatory cytokines, which is
237 an important limitation as hypoadiponectinemia is suspected to be the cause of atherosclerosis
238 and the development of cardiovascular disease.

239 5. Conclusions
240 Hypoadiponectinemia affects the lipid profile, especially by lowering HDL-c levels, and
241 stimulates lipolysis so that triglyceride levels are higher in obese adolescents.

242 6. Acknowledgments

243 None.

244 7. Funding

245 None

246 8. Conflict of interest

247 The authors declare no conflict of interest on behalf of the study.

248 9. Declaration of generative AI in scientific writing

249 Except for citations, the authors declared they did not use AI in the scientific writing.

250 10. References

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339
Figure Click here to access/download;Figure;Figure 1. flowchart of subjects recruitment.jpeg
Table Click here to access/download;Table (Editable
version);Hypoadiponectinemia_table.docx

Table 1. Subject’s characteristics

Characteristics x + SD Hypoadiponectinemia Normal P value
n=130 n=65 adiponectin
n=65
Age (months) 177.72 + 32.18 177.22 + 14.18 178.22 + 15.49 0.7021
Age group, n(%) 1.0002
< 192 months 113 (90) 57 (87.69) 56 (86.15)
> 192 months 17 (10) 8 (12.31) 9 (13.85)
Gender, n(%) 1.0002
- Male 82 (63.08) 41 (63.08) 41 (63.08)
- Female 48 (42.97) 24 (36.92) 24 (36.92)
Body weight (kg) 84.70 + 14.28 84.81 + 16.18 84.59 + 12.22 0.9281
Body height (cm) 161.29 + 7.01 160.34 + 7.40 162.24 + 6.51 0.1211
Waist 99.94 + 10.55 100.20 + 11.28 99.69 + 9.85 0.7851
circumference (cm)
Hip circumference 107.82 + 9.25 108.19 + 9.39 107.45 + 9.17 0.6501
(cm)
BMI (kg/m2) 32.42 + 4.49 32.85 + 4.67 32.00 + 4.30 0.2863
Total cholesterol 173.15 + 32.52 175.28 + 32.98 171.03 + 32.18 0.4591
(mg/dL)
LDL-c (mg/dL) 113.98 + 28.06 117.86 + 27.69 110.09 + 28.09 0.1151
HDL-c (mg/dL) 43.90 + 7.91 41.86 + 7.36 45.94 + 7.96 0.0031*
TG (mg/dL) 119.93 + 72.49 135.69 + 72.57 104.17 + 69.43 0.0033*
HOMA IR 4.75 + 3.37 4.89 + 3.76 4.60 + 2.95 0.8433
Insulin resistance 51(39.23) 27 (41.54) 24 (36.92) 0.7202
incidence, n(%)
Fasting insulin 22.67 + 15.09 23.39 + 16.05 21.96 + 14.16 0.5921
(µU/mL)
Fasting blood 83.96 + 7.49 82.80 + 8.10 85.14 + 6.70 0.8543
glucose (mg/dL)
Systolic-BP 125.46 + 13.62 125.08 + 13.64 125.85 + 13.79 0.7491
(mmHg)
Diastolic-BP 81.44 + 10.70 81.11 + 9.34 81.77 + 11.97 0.9813
(mmHg)
1
Independent sample T-test, 2Fischer exact test, 3Mann Whitney U test, *significant if P <0.05.
Abbreviation: BMI, body mass index; LDL-c, low density lipoprotein-cholesterol; HDL-c,
high density lipoprotein-cholesterol; TG, triglyceride; HOMA IR, homeostatic model
assesment of insulin resistance; BP, blood pressure.

Table 2. Correlation of hypoadiponectinemia with MetS and MetS risk factors

Characteristics n=130 Hypo- Normal Phi P value
adiponectinemia adiponectin
n=65 n=65
MetS 58 (44.62) 35 (53.85) 23 (35.38) 0.186 0.034
Central obesity 125 (96.15) 64 (98.46) 61 (93.85) 0.120 0.171
incidence, n(%)
 Hyperglycaemia 4 (3.08) 3 (4.62) 1 (1.54) 0.089 0.310
incidence, n(%)
Hypertriglyceridemia 60 (46.15) 37 (56.92) 23 (35.38) 0.216 0.014
incidence, n(%)
Hypo HDL-c 48 (36.92) 33 (50.77) 15 (23.08) 0.287 0.001
incidence, n(%)
Hypertension 57 (43.85) 27 (41.54) 30 (46.15) -0.047 0.596
incidence, n(%)
Abbreviation: HDL-c, high density lipoprotein-cholesterol.
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