The serum oxytocin correlated with serum leptin and body mass index in Japanese adolescents

Abstract

Oxytocin (OXT), a hypothalamic neuropeptide traditionally associated with reproduction and social bonding, has recently garnered attention for its role in regulating appetite and energy metabolism. To evaluate serum OXT levels and their association with adipokines in obese adolescents and those with type 2 diabetes mellitus (T2DM) compared to healthy controls. In this cross-sectional study, we included 27 participants—9 obese (median age [interquartile range] 10.0 [8.7–13.0] yr; men/women 3/6), 7 T2DM (16.0 [13.0–17.0] yr; 6/1), and 11 controls (10.8 [7.5–15.9] yr; 9/2). Serum OXT and adipokine levels were measured via the enzyme-linked immunosorbent assay. OXT levels were higher in patients with T2DM (130 [110–380] pg/mL) than in controls (85 [60–95] pg/mL; p = 0.002) and the obese group (125 [90–250] pg/mL) was intermediate between the two groups. Across all participants, OXT correlated positively with body mass index-standard deviation score (r = 0.51, p < 0.01) and leptin (r = 0.62, p < 0.001), and inversely with adiponectin (r = −0.39, p = 0.04). Leptin emerged as the strongest predictor of OXT variability (β = 0.53, p < 0.01). In adolescents with T2DM, serum OXT levels may reflect compensatory mechanisms in response to leptin resistance or metabolic stress.

Highlights

● Serum oxytocin correlated positively with BMI-SDS.

● Serum oxytocin correlated positively with leptin and inversely with adiponectin.

● Leptin emerged as the strongest predictor of oxytocin variability.

Introduction

Oxytocin (OXT), a neurohypophyseal peptide produced in the hypothalamic paraventricular nuclei and stored in the posterior pituitary, has traditionally been known for its roles in parturition and lactation (1). By revealing its involvement in social communication (2), mother-infant bonding (3), and interpersonal trust (4), recent research has expanded our understanding of OXT’s functions. Emerging evidence suggests that OXT plays a crucial role in feeding regulation and energy metabolism across species, including rodents, primates, and humans (5,6,7,8,9,10).

Studies have demonstrated that peripheral and central OXT administration can both decrease the body weight and fat mass of rodents with diet-induced obesity while preserving their lean mass (11, 12). In humans, clinical trials have shown that intranasal OXT may have a more pronounced effect on body weight reduction in individuals with higher initial body weight (9).

Adipose tissue functions as an endocrine organ, producing adipokines that inform the brain about the body’s long-term energy storage status (13). Among these, leptin plays a key role in regulating the body’s energy balance and weight through its effects on the central nervous system (13). This molecule has been implicated in the mechanism underlying increased serum OXT concentrations (14).

Given the interplay between OXT and adipokines in metabolic regulation, this study probed into the relationship between OXT and adipokines in adolescents with obesity and type 2 diabetes mellitus (T2DM).

Participants and Methods

Participants

Participants with simple obesity and T2DM were recruited from the pediatric clinics of Kawachi General Hospital. The study was conducted per the principles outlined in the Declaration of Helsinki, and the protocol was approved by the Kawachi General Hospital Review Board for Human Studies (approval number: 2019-003). Written informed consent was obtained from parents and assent was obtained from adolescent participants.

The study group comprised 9 simple obesity (3 men and 6 women; median age [interquartile range] 10.0 [8.7–13.0] yr) without medication use or evidence of endocrine malfunction. The control group included 11 participants (9 men and 2 women; 10.8 [7.5–15.9] yr) with normal blood pressure and no family history of diabetes mellitus. Diabetes was defined per the American Diabetes Association criteria (15). The T2DM group included 7 patients (6 men and 1 women; 16.0 [13.0–17.0] yr). Only one non-obese person was included in the T2DM group. Five patients with T2DM were treated with metformin (250–750 mg/d) and two patients with T2DM were treated with mixed-type insulin. The absence of microalbuminuria was determined by the urinary albumin-to-creatinine ratio (< 2.5 mg/mmol) and macrovascular disease by the absence of a relevant cardiovascular event history.

Sample collection and analysis

Fasting blood samples were collected in the morning, centrifuged at 4°C at 3000 rpm for 15 minutes, and stored at −80°C until analysis. The patient’s serum OXT concentration was measured using an OXT Enzyme Immunoassay kit (Arbor Assays, Michigan, USA), with intra-assay and inter-assay variations of 4.3%–5.2% and 7.7%–10.0%, respectively.

Serum leptin, adiponectin, and resistin levels were measured using enzyme-linked immunosorbent assay kits (Proteintech, Rosemont, IL, USA and R&D Systems Inc., Minneapolis, ML, USA, respectively). The mean intra-assay coefficients of variation were 3.7%, 3.5%, and 5.9% with lower detection limits of 2.0 pg/mL, 0.246 ng/mL, and 0.012 ng/mL for leptin, adiponectin, and resistin, respectively.

Definitions of overweight or obesity

Participants’ physiques were assessed using the percentage of overweight (POW), which is calculated as follows:

POW (%) = 100 × (measured weight − standard weight)/standard weight.

The standard weight was determined from the 2000 Annual Report of School Health Statistics (Japanese Ministry of Education, Culture, Sports, Science and Technology), based on the age- and sex-specific weight for height. The Japanese standard weight was calculated using an approximated equation derived from the height and weight distributions at each age (16).

The criterion for overweight/obesity was a POW ≥ 20% (≥ 120% of the standard weight). The normal range for school-age children is between −20% and 20%. The POW method was chosen over BMI percentiles because it is more appropriate for school-age children, avoiding the misclassification of tall students as overweight and short students as underweight (17). Simple obesity was defined as a person’s weight exceeding the normal range due to energy intake exceeding energy expenditure, excluding T2DM and symptomatic obesity.

Obesity defined by POW in this study approximates to the BMI standard established by the Japanese Association for Human Auxology (18). It was defined as a BMI equal to or greater than the 90^th percentile.

Statistical analysis

Statistical analyses were performed using JMP 6 (SAS Institute Inc., Cary, NC, USA). Quantitative data are expressed as the median with its interquartile range (IQR) for non-normality distributed variables. Between-group comparisons of continuous variables were conducted using Wilcoxon’s test. Associations between serum OXT and other continuous variables were examined using Spearman’s correlation and univariate regression analysis. Categorical variables were compared using the chi-square test.

Stepwise multiple logistic regression was used to identify independent predictive effects of variables (e.g., age, sex, BMI-SDS, leptin, adiponectin, and resistin levels) on serum OXT levels. Multivariate modeling used forward stepwise regression, with p = 0.25 as the criterion for entry into the model and p = 0.10 as the criterion to remain in it.

Results

In this study, we included seven adolescents with T2DM (6 men, 1 woman; median [IQR] disease duration: 4.5 [3.7–6.0] yr) and nine with simple obesity (3 men, 6 women). The key anthropometric and biochemical parameters of our study participants are outlined in Table 1. The participants in the T2DM group were significantly older than those in the control and obese groups; however, no age differences were found between the obesity and control groups. Serum OXT levels were significantly higher in both the T2DM and obesity groups compared with the control group (Table 1). Serum leptin levels were elevated and adiponectin levels were reduced in the T2DM and obesity groups compared to the control group (Table 1). No significant differences in serum OXT, leptin, adiponectin, or resistin levels were observed between the T2DM and obesity groups. Serum resistin did not differ significantly among the three groups.

Table 1. Anthropometric and biochemical characteristics of three groups.

Because age and sex ratios varied slightly across the groups, results were reanalyzed after adjusting for these factors. Neither adjustment for age and sex nor adjustment for diabetes medication use altered the associations observed between OXT and leptin.

Across all participants, the OXT level showed a significant positive correlation with BMI-SDS (r = 0.513, p = 0.0063; Fig. 1) and the leptin level (r = 0.621, p = 0.0005; Fig. 2), and a negative correlation with the adiponectin level (r = −0.396, p = 0.0407; Fig. 3). Across all participants, BMI-SDS showed a statistically significant positive correlation with the serum leptin level (r = 0.625, p = 0.0011; Fig. 4), and a significant negative correlation with the serum adiponectin level (r = −0.534, p = 0.0060; Fig. 5).

Fig. 1.

The correlation between the body mass index-standard deviation score (BMI-SDS) and the serum oxytocin level across all participants (r = 0.513, p = 0.0063). Red circles, control participants; blue circles, participants with simple obesity; green circles, participants with type 2 diabetes mellitus.

Fig. 2.

The correlation between the serum leptin level and the serum oxytocin level across all participants (r = 0.621, p = 0.0005). Red circles, control participants; blue circles, participants with simple obesity; green circles, participants with type 2 diabetes mellitus.

Fig. 3.

The correlation between serum adiponectin level and serum oxytocin level across all participants (r = −0.396, p = 0.0407). Red circles, control participants; blue circles, participants with simple obesity; green circles, participants with type 2 diabetes mellitus.

Fig. 4.

The correlation between the BMI-SDS and the serum leptin level across all participants (r = 0.625, p = 0.0011). Red circles, control participants; blue circles, participants with simple obesity; green circles, participants with type 2 diabetes mellitus.

Fig. 5.

The correlation between the BMI-SDS and the serum adiponectin level across all participants (r = −0.534, p = 0.0060). Red circles, control participants; blue circles, participants with simple obesity; green circles, participants with type 2 diabetes mellitus.

Stepwise multivariable regression identified the leptin level (F = 11.49, p = 0.0026) and BMI-SDS (F = 9.64, p = 0.0051) as independent predictors of the OXT level. OXT was the most significant coefficient for BMI-SDS (p = 0.006, β = 0.53).

Discussion

This study demonstrates significant correlations between the serum OXT level and BMI-SDS, leptin, and adiponectin levels in adolescents with obesity and T2DM. Specifically, the OXT level was positively correlated with BMI-SDS and the leptin level, and it was inversely correlated with the adiponectin level.

Our findings align with reports of elevated OXT levels in severely obese adults (19, 20), suggesting a potential association between OXT and obesity-related metabolic dysregulation. In adolescents with T2DM, elevated OXT could reflect a compensatory response to leptin resistance, similar to mechanisms proposed in metabolically dysfunctional adults. Preclinical studies support a role for OXT in energy balance, showing that high OXT levels reduce body weight, suppress energy intake, and promote lipolysis (21,22,23,24,25,26). This compensatory rise in OXT may be more evident in metabolically healthier obese individuals, who are relatively free of insulin resistance.

However, previous research on circulating OXT levels in obesity and T2DM has yielded inconsistent results (19, 20, 27,28,29,30,31,32). Some studies associate higher OXT concentrations with greater BMI and fat mass (30), while others—particularly in participants with metabolic syndrome or glucose dysregulation—report lower OXT and negative correlations with metabolic risk factors (28, 31,32,33). These discrepancies may be explained by differences in age, sex, ethnicity, and metabolic status, all of which are known to influence OXT secretion. Adolescence, in particular, is a developmental stage marked by substantial endocrine changes, including pubertal fluctuations in leptin, adiponectin, and insulin sensitivity. Leptin rises during early puberty in boys before declining as testosterone increases, whereas in girls it continues to rise (34, 35). Adiponectin levels typically decrease during puberty and later recover (36). In addition, puberty-associated increases in insulin resistance may also influence OXT regulation (37,38,39).

Pharmacological factors are another consideration. Antidiabetic medications can alter ciculating leptin, adiponectin, and OXT levels, although the direction and magnitude of these effects vary across hormones and treatments. For example, some interventions that reduce fat mass or improve insulin sensitivity have been associated with lower leptin levels (40).

The metabolic role of OXT appears to be context dependent. OXT interacts with leptin signaling within hypothalamic pathways regulating appetite (14, 23, 41,42,43) and energy expenditure, which suggests it may function both as a compensatory response and as a regulatory hormone.

In this study, serum OXT was elevated in both T2DM and obesity groups compared with controls, but no significant differences emerged between T2DM and obesity. Thus, it remains unclear whether the increase is primarily attributable to diabetes, obesity, or their overlap.

In our cohort, OXT emerged as the strongest independent correlate of BMI-SDS by regression analysis, suggesting that leptin’s influence on BMI-SDS may be mediated, at least in part, through OXT and adiponectin. This finding highlights the importance of the neuroendocrine axis, with OXT serving as a potential modulator of metabolic adaptation in adolescents with obesity and T2DM.

This study has several limitations. The relatively small sample size may limit statistical power and the generalizability of the findings. The cross-sectional design also precludes any inference of causality. Potential influence of the higher age of the T2DM group, as compared with the other groups, cannot be excluded with respect to the study results. Furthermore, the lack of standardized OXT assay and sample handling protocols complicates interpretation of peripheral OXT measurements, which may not accurately reflect central OXT activity.

Further research involving larger, well-characterized cohorts and standardized OXT measurement techniques is warranted to elucidate the regulatory role of OXT, clarify compensatory versus causative mechanisms, and determine its potential as a biomarker or therapeutic target in obesity and T2DM.

Conclusion

We observed significantly elevated OXT levels in adolescents with T2DM compared to controls and found significant correlations between OXT, BMI-SDS, leptin, and adiponectin levels. These findings suggest that OXT, in conjunction with leptin, plays a role in regulating body size and metabolism in adolescents.

Conflicts of interest

The authors have no conflicts of interest to declare.