Sex Differences in Neuropeptide Y Serum, But Not in Fat Intake and Body Mass Index
Phase: NA
Conditions: Nutrient Deficiency
Sponsor: Universitas Sumatera Utara

Sex Differences in Neuropeptide Y Serum, But Not in Fat Intake and Body 
Mass Index 
 
Dina Keumala Sari1*, M. Ichwan2, Dewi Masyithah3, Ridha Dharmajaya4, and Alfi Khatib5 
1Department of Nutrition, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia, 
e-mail address: dina@usu.ac.id; Livedna ID: 62.14510 
2Department of Pharmacology, Faculty of Medicine, Universitas Sumatera Utara, Medan, 
Indonesia, email: m.ichwan@usu.ac.id 
3Department of Parasitology, Faculty of Medicine, Universitas Sumatera Utara, Medan, 
Indonesia, email: dewi2@usu.ac.id 
4Department of Neurosurgery, Faculty of Medicine, Universitas Sumatera Utara, Medan, 
Indonesia, email: ridha@usu.ac.id 
5Kulliyah of Pharmacy, International Islamic University Malaysia, Malaysia, email: 
alfikhatib@iium.edu.my 
*Corresponding author; Email: dina@usu.ac.id; Cellular phone: +62 81397177693; +62 61 
8212296 
Livedna ID: 62.14510; ORCID ID orcid.org/000-0002-1442-5304 
 
 
Date: November 18th, 2020 
 
 
 

Sex Differences in Neuropeptide Y Serum, But Not in Fat Intake and Body 
Mass Index 
Abstract 
Background: One’s appetite has a role in controlling food intake and maintaining energy 
balance, but its effect on body metabolism related to obesity is still questionable. The purpose of 
this study was to determine the levels of neuropeptide Y in healthy people and to see differences 
in gender and anthropometric parameters. The hypothesis of this study was that there would be 
differences in neuropeptide Y levels in groups with gender and anthropometric parameter 
differences. Methods: This study was a cross-sectional study involving 62 study subjects, male 
and female, who did not have chronic diseases or metabolic disorders. This research was 
conducted from April to September 2020. The parameters examined in this study were 
neuropeptide Y levels and anthropometric parameters. The statistical analysis performed was the 
Mann-Whitney test to see the differences between groups. Results: The mean age of the research 
subjects was 40.48 ± 10.85 years, with the same ethnic distribution. The distribution of men and 
women was more women than men. Based on anthropometric examination, it was found that 
obesity nutritional status was more common in the female group than in the male group; 
however, serum neuropeptide Y levels were found to be significantly different between male and 
female groups (male group was higher). Conclusions: The study found significant differences in 
serum neuropeptide Y levels in male and female groups. 
 
 
Keywords: obesity; appetite; neuropeptide; orexigenic; fat; energy; gender 
 
Background 
Motivation and appetite are important phenomena in human life to maintain energy 
balance and body weight 1, 2. Increased appetite temporarily or permanently leads to weight gain 
and thus the risk of obesity is greater 3, 4. The hypothalamus as the center of hunger and fullness 
produces neuropeptide Y as a potent anabolic peptide that increases appetite and reduces energy 
consumption 1, 5, 6. 
Previous studies have shown no difference in neuropeptide levels in men and women, but 
some have shown different results 7-9. One study linked metabolic parameters, such as body mass 
index and blood pressure, and found no differences in neuropeptide Y levels between the sexes, 
which may have been due to a complex mechanism that still needs further research 10, 11. 

Neuropeptide Y is a key orexigenic neuropeptide that regulates adiposity by reducing 
energy storage and utilization 12-14. Fasting conditions or low caloric intake stimulate 
neuropeptide Y expression, which increases appetite 12, 13. Neuropeptides are expressed mostly in 
the hypothalamus and in peripheral tissues such as white fat tissue and bone cells, which 
indicates that there are several other physiological functions apart from maintaining energy 
balance 12, 15, 16. 
After reviewing the relevant research, it is clear that the function of neuropeptide Y 
research is related to the accumulation and mobilization of lipids, as. These regulate peroxisome 
proliferator-activated receptor gamma 2 and hormone sensitive lipase (HSL) 
16, 17. If 
neuropeptide Y levels are reduced, the factors that cause imbalance age-related adipose tissue 
metabolism increases, such as decreased increased inflammation, decreased de novo lipogenesis 
in visceral fat, and decreased thermogenic activity in subcutaneous fat 14, 17. Rat studies suggest 
that low and high levels of neuropeptide Y are sex dependent; however, studies in humans do not 
find the same results. Low levels of neuropeptide Y did not affect adiposity in mouse studies, 
whereas some studies have found it humans while some have not 17-19. For this reason, it is 
interesting to investigate whether there is a difference in neuropeptide Y levels in the associated 
factors in male and female groups. 
This study aimed to determine whether there were differences in neuropeptide Y levels in 
certain groups, namely social factors (age and sex) and metabolic parameters (body mass index, 
energy intake, and fat intake). This study determined the associated factors that will form the 
basis for future research. This study also provided further information regarding the role of 
neuropeptide Y on obesity. 
Methods 

Study design 
This study included a cross-sectional design that took sociodemographic data (i.e., age, 
ethnicity, sex, occupation, history of father, and mother fat), anthropometric examinations (i.e., 
body mass index and abdominal circumference), examination of daily food intake (i.e., energy, 
intake fat, protein intake, and carbohydrate intake per day), and serum neuropeptide Y levels in 
the study subjects. 
All research subjects were collected from the same area, namely in areas far from urban 
areas (i.e., Dusun III, Simpang Dolok Village, Datuk Lima Puluh District, Batu Bara District, 
and North Sumatra, Indonesia). We avoided subjects from urban areas because they were have a 
diverse diet. This research was conducted from April to September 2020, after the COVID-19 
pandemic had spread across the globe, yet the study location has not had any COVID-19 cases. 
During the data collection period, it was also carried out by implementing strict health protocols.  
Participants 
 
The included research subjects were healthy men and women aged 20-60 years old. 
Exclusion criteria were pregnant women, nursing mothers, impaired kidney and liver function, 
chronic disease, or other metabolic disorders. The process of finding research subjects came by 
appealing to the local community health center, as well as spreading word of mouth, wherein the 
subjects came voluntarily. When we were selecting research subjects, 96 research subjects were 
enrolled but only 62 research subjects passed the exclusion criteria. 
The research subjects had also read the explanation about the research and were willing 
to take part in the research by signing the informed consent form. This research procedure and 
protocol was approved by the Research Ethics Committee of the University of North Sumatra, 
Indonesia, with the certificate number: No. 61 / KEP / USU / 2020. 

Anthropometric examination 
Anthropometry included height (to the nearest 0.5 cm), weight (to the nearest 0.1 kg), and body 
mass index (calculated as kg/m2). Categorized body mass index (BMI) was based on Asia 
Pacific, which were <18.5 kg/m2 classified as underweight, 18.5-22.9 kg/m2 classified as 
normoweight, 23-24.9 kg/m2 classified as overweight/at risk, 25-29.9 kg/m2 classified as obese I, 
and >30 kg/m2 classified as obese II.20 
We examined waist circumference using a standardized measuring tape in centimeters. 
The category of abdominal circumference was different between men and women. For men, less 
than 90 cm was classified as normal and more than 90 cm was classified as central obesity. For 
women, less than 80 cm was classified as normal and more than or equal to 80 cm was classified 
as central obesity. 20 
Nutrient intake assessment 
Assessment of nutrient intake was based on food recall for two days (one day for weekday and 
one day for weekend), including energy, protein intake, fat intake, carbohydrate intake, and 
percentage of fulfilment according to the Indonesian Recommended Dietary Allowances (RDA) 
2019. Calculation were conducted using the Nutrisurvey application (2005), which included 
Indonesian foods. 
The following categorizations were determined: for calorie intake, <2500 calories per day 
was low and 2500 calories per day was normal; for protein intake, <60 grams per day was low 
and 60 grams per day was normal; for carbohydrate intake, <400 grams per day was low and 
400 grams per day was normal; for fat intake, <65 grams per day was low and 65 grams per 
day was normal; for fiber intake, <25 grams per day was low and 25 grams per day was 
normal21.  

Neuropeptide Y examination  
This examination was conducted by drawing blood serum from research subjects and performing 
centrifugation with 2000-3000 revolutions per minute (RPM) for 20 minutes. Furthermore, we 
carried out blood serum tests to check neuropeptide Y levels using the Human Neuropeptide Y 
Enzyme-link Immunosorbent Assay (ELISA) kit (Thermo Fisher Scientific brand, Waltham, 
MA, USA) (Bioassay Technology Laboratory, Shanghai, China). 
Statistical analysis 
Data were analyzed using version 11.5 of the IBM-SPSS statistical program (IBM Corp., 
Chicago, IL). Categorical variables were expressed as percentages. Normally distributed 
continuous variables were expressed as mean ± SD, whereas non-normally distributed 
continuous variables were expressed as median (minimum-maximum). To compare the two 
groups, the independent T statistic test was used if the distribution was normal and the Mann–
Whitney test was used if data were not normally distributed.  
Results 
Baseline characteristics of the study population 
This oldest population of research subjects were aged 41-50 years old (35.5%) and youngest 
population were aged 20-30 years old (19.4%). Ethnic groups, namely the Indonesian Malay and 
Batak tribes, were evenly divided into the two groups. These two tribes are the largest ethnic 
group found in North Sumatra, Indonesia (Table 1). 
Table 1 shows that the majority of subjects were women (56.5 vs. 43.5%), and the most 
common occupation was housewives (37.1%). The study was located at a rural area so that the 
occupation of most adult women were housewives. Most males in this study were laborers 
(27.5%), which is a notable financial job in this region.  

The history of obesity from patients’ parents was also asked to see if there was a 
relationship to obesity in adulthood. Most patients did not have parents with obesity (83.9 vs. 
72.6%) (Table 1). The analysis stated that there was no significant relationship between the 
incidence of obesity and a history of obesity in the father (p = 0.738) and mother (p = 0.581). 
Characteristic data on sex differences 
This study compared age and anthropometric data between men and women, aiming to see if 
there were differences between these two groups. This study showed that no significant 
differences were found between men and women in terms of age. In both groups, most patients 
were in the 41-50 age group (Table 2). 
 
An anthropometric examination did not show any differences between the two groups of 
men and women. The obese group was more common in the female group than in the male 
group, but there was no significant difference (Table 2). Table 2 also shows that there was no 
abdominal circumference difference between men and women, yet the percentage of abdominal 
circumference exceeded the normal limit more in the female group (54.3%). 
In Table 3, based on food intake for two days, there was no difference between men and 
women, except in total energy (p = 0.019), wherein the average energy intake for women is 
higher than that of men. The intake of fat, protein, and carbohydrates also showed that the intake 
of women was higher than men but did not show a significant difference. 
Table 4 shows the differences in neuropeptide Y levels in several parameters related to 
neuropeptide Y activity as orexigenic. The mean neuropeptide Y levels of all study subjects were 
277.81±289.31 ng / L, with the minimum value being 71.5 ng / L. The median value was 116 ng 
/ L and the maximum value was 981 ng / L. The data were not normally distributed. The 
neuropeptide Y level with the 5th percentile was 78.2 ng / L; the 10th percentile was 81.69 ng / 

L; the 25th percentile was 90.48 ng / L; the 50th percentile was 116 ng / L; the 75th percentile 
was 428 ng / L; the 90th percentile was 872.1 ng / L; and the 95th percentile was 974.55 ng / L. 
The range of neuropeptide Y levels in this study was 91.2 to 422 ng / L. Table 4 shows that the 
differences in neuropeptide Y levels were only found in the male and female groups. This study 
did not show any significant differences between the obese or non-obese groups, nor the high 
and low fat intake groups. 
 
Based on the results of this study, it can be seen that neuropeptide Y showed significant 
differences in the male and female groups, yet not in the obese or fat intake groups. This 
difference requires further discussion. 
Discussion  
Motivation and appetite are the basis for regulating energy balance and weight, and can 
determine whether a person is obese or not 13, 14, 17. Obesity is caused by consuming energy that 
exceeds basic needs; however, becoming obese is also influenced by several factors apart from 
high serum neuropeptide Y levels, including the availability of available food ingredients and 
diet. Residents in rural areas who are far from a high-fat diet will naturally consume the food 
available to them. This differs from urban areas that have more diverse foods.  
High energy intake can be attributed to consuming too much saturated fat from red meat, 
animal fat, palm oil, or deep fried foods. High-fat food ingredients are found in fast food, which 
is generally found in urban areas. However, in locations far from urban areas, excess energy 
intake generally comes from high carbohydrate consumption, which consists of rice, noodles, or 
sweet potatoes. Excess glucose is stored in the form of fatty acids. The role of neuropeptide Y 
does not seem to focus solely on high fat intake, but, in our study, it appeared that higher levels 
of neuropeptide Y were found in the male group. 

 
Neuropeptide Y is a orthigenic peptide that plays an important role in life extension. It is 
also restricted by calories and the mechanism is less clear.17 Low neuropeptide Y levels 
combined with calorie restriction lead to high mortality associated with lipolysis and 
lipodystrophy. Low levels of neuropeptide Y cause active lipolysis and thermogenic signals, i.e., 
Beta3 adrenergic receptors and lipase sensitive hormones in white adipose tissue. The end result 
is a negative energy balance.12, 17 The role of neuropeptide Y includes regulating lipid metabolic 
homeostasis and survival via lipolysis and thermogenesis control pathways in a negative 
balance.12, 13, 22  
 
Neuropeptide Y is an appetite stimulator that increases fat collection through insulin and 
corticosteroid secretion, increases hepatic glucose utilization, reduces muscle glucose, increases 
glucose utilization by white fat tissue, activates brown fat tissue metabolism, decreases 
sympathetic activity, increases parasympathetic activity, and decreases thermogenesis2, 3, 14, 23. 
Neurons containing neuropeptide Y become active during negative energy balance conditions 
such as hunger, dietary restrictions, breastfeeding, physical exercise, and uncontrolled diabetes 4, 
24, 25. Neuropeptide Y provides changes in eating behavior, but the role of neuropeptide Y 
receptors and their expression also have an effect on increasing appetite.26, 27 Seven subtypes of 
neuropeptide Y receptors, namely Y1 to Y7, are associated with stimulating appetites.  
 
Neuropeptide Y changes one’s energy balance in a positive direction by increasing food 
intake, limiting energy expenditure, and reducing thermogenesis in brown fat tissue 25, 28. In 
parallel with this process, neuropeptide Y also facilitates fat storage in white fat tissue through 
increased insulin activity 2, 18, 25. However, in this study, there are various factors that affect 
increased food intake. Based on our analysis, high levels of neuropeptide Y in serum did not 
show a direct relationship to obesity and fat intake. The condition of food shortages can be a 

direct cause of this, considering that most research subjects are as laborers and housewives who 
live in rural areas. 
Although the age of patients in this study was predominantly older (41–60), the total 
calorie intake was still low. The female group showed more obesity than the male group, and the 
female group also had larger abdominal circumferences. For women with hormonal influences, 
the combination of food availability and inactivity caused greater obesity than men, even though 
the serum neuropeptide Y levels were found to be significantly lower than men. This shows 
several factors that greatly influence the incidence of obesity in a person. In addition, there were 
hereditary factors that influenced obesity, but this study showed that, when a person entered 
adulthood, there were multifactorial occurrences that increased their likelihood of becoming 
obese. High appetite also caused neuropeptide Y to be released by the hypothalamus29. 
 
The history of obese parents did not show an association with patient obesity, although 
most patients did not have obese parents 30, 31. Family history of obesity or metabolic disease 
played an important role, especially in childhood, as it was associated with obesity 32, 33. 
Multifactorial lifestyles that provide an availability to consume high-fat or high-carbohydrate 
foods, encourage a lack of physical activity, breakfast habits, or genetic polymorphisms, were 
independent of high and low levels of neuropeptide Y released by the hypothalamus 32, 34-36. All 
conditions are related to obesity and mostly impacted children entering adulthood. Various 
processes can make a person obese, including the role of neuropeptide Y. 
In this study, women had lower levels of neuropeptide Y than men. Fat intake was 
unrelated to these findings. Previous studies suggested that women had lower expressions of 
neuropeptide Y than men in non-stressed states, especially when their brains were associated 
with stress. Further, estrogen levels play a potential role in its regulation 11, 37-39. Another 

possibility for appetite control is related to neuropeptide Y, which regulates depressive-like 
behavior. The effects of anxiety, however, are more common in men 37, 40, 41. Therefore, high 
levels of neuropeptide Y affect appetite if intake is not excessive. 
Gender plays an important role in the development of stress-induced psychological 
disorders 37. Stress causes more traumatic disorders in men than in women. However, for other 
types of neuropsychiatric disorders, women have twice the vulnerability than men, such as post-
traumatic stress disorder, depression, anxiety, and anorexia nervosa.37 This also triggers the 
possibility that, in this study, there was no visible increases in body weight or high fat intake in 
the male group despite higher levels of neuropeptide Y in women. 
This study has limitations. First, research subjects do not easily remember what they ate 
or drank on a given day and some of the subjects are afraid to report what they have consumed, 
especially in the male group. Future research should attempt to obtain more accurate data. That 
said, our findings provide important insights into the role of neuropeptide Y in the occurrence of 
obesity, especially in sex differences. This requires further research on the role of neuropeptide 
Y in men to overcome obesity.  
Conclusions  
The study found that there were significant differences in serum neuropeptide Y levels in the 
male and female groups, with neuropeptide Y levels being higher in men than in women. 
 
Acknowledgement 
The authors would like to thank Dr. Muhammad Nizar and Kepala UPT Puskesmas Lima Puluh 
for assisting in participant recruitment in Village III, Desa Simpang Dolok, Kecamatan Datuk 
Lima Puluh, Kabupaten Batubara, North Sumatera, Indonesia. We also would like to thank the 
research volunteers who participated in this study. 
Authors contributions 
Dina Keumala Sari (DKS):Conceptualization, Data curation, methodoly, and funding 
acquisition. M. Ichwan (MI): Formal analysis, Project administration, Resources, Investigation.  

Dewi Masyithah (DM): Software, Supervision, and Validation. Ridha Dharmajaya (RD): 
Validation, Writing-original draft and review-editing. All authors have read and approved the 
final manuscript. None of the authors report a conflict of interest related to this study. 
Funding 
This project was funded, in part, by the Lembaga Penelitian Universitas Sumatera Utara 
according to TALENTA Universitas Sumatera Utara, year 2020, no. 4142/UN5.1.R/PPM/2020, 
date: 27 April 2020. 
Availability of data and materials 
All data generated or analyzed during this study are included in this article. 
Ethics approval and consent to participate 
All participants knowledgeably consented to participate in this study. Procedures and protocols 
used were approved by the Universitas Sumatera Utara Ethical Committee, No. 
61/KEP/USU/2020. 
Competing interests 
The authors declare that they have no competing interests. 
 
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Table 1. Socio-demographic data of all subjects.  
Characteristics  
 
n(%)  
Mean±SD 
Age (years) 
  20-30 
  31-40 
  41-50 
  51-60 
 
 
12(19.4) 
15(24.2) 
22(35.5) 
13(20.9) 
40.48±10.85 
 
Ethnics 
  Indonesian Malay 
  Bataknese 
 
 
31(50) 
31(50) 
 
Gender  
  Male 
  Female 
 
 
27(43.5) 
35(56.5) 
 
Occupation 
  Housewife 
  Labour  
  Farmer 
 
23(37.1) 
17(27.5) 
9(14.5) 
 

  Government staff 
  Student  
 
8(12.9) 
5(8) 
Father’s obesity history  
  No 
  Yes 
 
 
52(83.9) 
10(16.1) 
 
 
Mother’s obesity history 
  No 
  Yes  
 
 
45(72.6) 
17(27.4) 
  
 
 
Notes:  
Age data presented in mean and standard deviation 
Others presented in number of the subject and percentage 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2. Characteristic data of the subjects based on anthropometry status 
Characteristics of 
anthropometry status 
 
 
 Male  
(mean±SD) 
Female  
(mean±SD) 
p 
Age (years) 
Categorized, n(%): 
  20-30 
  31-40 
  41-50 
  51-60 
 
41.89±10.98 
 
4(6.5) 
6(9.7) 
9(14.5) 
8(12.9) 
 
39.40±10.78 
 
8(12.9) 
9(14.5) 
13(21) 
5(8.1) 
0.375 
 
0.501 
Body mass index (kg/m2) 
Categorized, n(%):  
  Underweight 
  Normal 
  Overweight 
  Obese 
 
28.66±16.31 
 
2 (3.2) 
10(16.1) 
2(3.2) 
13(21.0) 
25.15±4.12 
 
1(1.6) 
13(21) 
5(8.1) 
16(25.8) 
0.793 
 
0.727 
Waist circumference (cm) 
Categorized for male, n(%): 
83.67±10.3 
 
82.6±11.92 
 
0.713 

  <90 cm 
  >90 cm 
 
Categorized for female, n(%): 
  <80 cm 
  >80 cm 
22(81.5) 
5(18.5) 
 
 
 
 
 
 
 
 
 
16(45.7) 
19(54.3) 
 
Notes: 
Numeric data were presented in mean and standard deviation 
Categorical data were presented in number of the subject and percentage 
The analysis test for age and abdominal circumference used independent t test 
Mann Whitney test was used to analyze body mass index 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3. Characteristic data of the subjects based on food intake 
Characteristics of food intake 
 
 
 Male  
(mean±SD) 
Female  
(mean±SD) 
p 
Energy intake 
Categorized, n(%): 
Less than 2500 kal/day 
More than 2500 kal/day 
 
1105.32±577.77 
 
23(37.1) 
4(6.5) 
1597.22±939.89 
 
34(54.8) 
1(1.6) 
0.019* 
 
0.086 
Fat intake 
Categorized, n(%): 
Less than 65 gram/day 
More than 65 gram/day 
39.21±25.56 
 
4(6.5) 
23(37.1) 
 
44.13±41.42 
 
6(9.7) 
29(46.8) 
0.809 
 
0.805 
Protein intake 
Categorized, n(%):  
Less than 60 gram/day 
More than 60 gram/day 
 
44.91±18.48 
 
18(29) 
9(14.5) 
 
56.10±29.73 
 
29(46.8) 
6(9.7) 
 
0.056 
 
0.12 
Carbohdrate intake 
Categorized, n(%):  
Less than 400 gram/day 
39.21±25.56 
 
27(100) 
44.13±41.42 
 
27(100) 
0.809 
 
- 

More than 400 gram/day 
 
- 
- 
 
Notes: 
*Significant: p<0.005  
Numeric data were presented in mean and standard deviation 
Categorical data were presented in number of the subject and percentage 
The analysis test for age and abdominal circumference used independent t test 
Mann Whitney test was used to analyze body mass index 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tabel 4. Difference in mean of Neuropeptide Y in groups 
Neuropeptida serum 
level (ng/L) 
n(%) 
Median 
(minimum-maximum) 
Mean ± SD 
p 
In: 
Male group 
Female group 
 
 
27(43.5) 
35(56.5) 
 
121(71.5-981) 
100(71.5-938) 
 
348.37±330.09 
223.38±244.62 
 
0.036* 
In: 
Non-obese group 
Obese group 
  
 
33(53.2) 
29(46.8) 
 
117(71.5-981) 
116(77.8-981) 
 
278.18±301.11 
277.39±52.1 
 
0.447 
In: 
Low fat intake group 
High fat intake group 
 
 
52(83.9) 
10(16.1) 
 
116(71.5-981) 
118.5(80.5-981) 
 
270.18±279.98 
317.45±347.85 
 
0.66 
Notes: 
Data reprensted in mean±standard deviation (SD) 
Using Mann-Whitney test 
*: significant; p<0.05 
 
 

Approval Sheet After Explanation (Informed Consent) 
 
My Informed Consent Sheet signed below,  
Name :  
Age :  
Gender :  
 
 Has been clearly explained by the researcher about the study “Sex Differences in 
Neuropeptide Y Serum, But Not in Fat Intake and Body Mass Index”, so I hereby voluntarily and 
without coercion stated : 
 
Willing to be included in the study.  
 
Such is this statement to be used as necessary. 
 
Sincerely, 
 
_____________