This study investigated the difference or/and relationship of clinical features and metabolites between MHO and MUO in adolescents. To investigate the clinical features of MetS in obese adolescents, this study divided the participants into MHO and MUO groups, according to the IDF criteria. The results revealed that there were significant differences between the adolescents in the MHO group and those in the MUO group in terms of laboratory measurements, IR assessment index (i.e., HOMA-IR and TyG index), and lipid profiles. Furthermore, there were significant differences in the 3 ACs, 5 AAs, Gln/Glu ratio, 3 BAs, and 2 GPLs between the adolescents in the MHO group and those in the MUO group. The results showed that several metabolites were associated with the prevalence of MUO in adolescents. Additionally, several metabolites were inversely correlated with MHO in adolescents of the MUO group. Thus, MUO adolescents have metabolic characteristics despite the same obesity.
Despite the same obese adolescents (even nutrition intake was not significantly different), the obesity or MetS diagnosis factors (e.g., height, weight, FFM, BMI%, weightth, SBP, and DBP) were significantly different between the adolescents of the MHO group and the adolescents of the MUO group. These factors are known to be good biomarkers of obesity and MetS (27, 28). In the current study, AST and ALT were positively correlated with His in the adolescents of the MHO group, whereas in the adolescents of the MUO group, an inverse correlation was found. Obese individuals or those with T2DM or IR had a high level of AST and ALT (29). Some research has shown that although levels of AST and ALT are increased (30), His concentrations are lower (31) in patients with CVD. However, research reported that there was an increase in the liver AST following an intake of His supplementation by obese women with MetS (32). Further research is warranted to understand the correlation between AST, ALT, and His in obese or MetS adolescents.
Unlike the HOMA-IR, the TyG index was significantly higher in the adolescents of the MUO group than in the adolescents of the MHO group. Moreover, the MUO prevalence ORs of the TyG index were 2.046-fold higher for each quartile. Recently, the TyG index is being considered as an IR assessment index along with HOMA-IR (33). In addition, studies have reported that the TyG index is more appropriate for the diagnosis of T2DM than weight gain (34). Thus, the TyG index could be a good biomarker of MetS in obese adolescents.
The C2, C3-OH, and C5-M-DC of ACs were significantly different between the adolescents of the MHO group and those of the MUO group. Unlike in adolescents of the MHO group, the C2 was positively correlated with DBP in adolescents of the MUO group. Additionally, the MUO prevalence OR of C2 was 1.606-fold higher for each quartile. ACs have a trend to increase the level of individuals who have a risk of obesity and MetS (35, 36). ACs are divided by the length of carbon chains in the molecular structure, such as free carnitine; C0, short-chain; C2–C5, medium-chain; C6–C12, and long-chain C14–C18 (37). C2 of short-chain ACs has a positive correlation with BMI in patients with T2DM (38, 39). Furthermore, C2 has been associated with SBP (40). Some research showed that the level of C3-OH was significantly high in patients with peripheral artery disease, diabetic nephropathy, and DM than that in a control group (41, 42). A study showed that C5-M-DC was associated with IR, in mice with DM (43). In addition, C5-M-DC has a strong relationship between glomerular filtrating rate and creatinine in patients with CVD (44). Furthermore, the current study investigated the predictors of the MUO adolescent's prevalence as ACs by the length. The results depicted that the prevalence ORs of the short-chain ACs were significantly greater than ORs of the MUO occurrence, compared with each quartile of the metabolites (Table S1, Additional file 1). Some research suggested that an increase of short-chain ACs was associated with MetS such as T2DM and obesity (45, 46). Therefore, C2, C3-OH, and C5-M-DC of ACs may be metabolic biomarkers of related MetS in obese adolescents.
The Gln, His, Lys, Ser, and Gln/Glu ratios were significantly lower in the adolescents of the MUO group than in the adolescents of the MHO group. On the contrary, Ala was significantly higher in the adolescents of the MUO group compared with the adolescents of the MHO group. According to a study, levels of Ala were high in obese individuals than normal-weight individuals (47). Furthermore, Ala is a gluconeogenic substrate secreted by skeletal muscle at higher levels in patients with DM (48). Some studies have suggested that Ser has therapeutic potential for DM (49), such as improved regulation of blood glucose (50) and insulin secretion (51). Lys levels were decreased in MetS individuals (in particular, cardio-metabolic features and inflammatory biomarkers), as per a study (52). Another study suggested that Lys has potential protective effects against MetS (53). These results are in line with the results of our study. Therefore, Ala, Gln, His, Lys, and Ser might be good biomarkers of MetS in obese adolescents. According to Cheng et al. (54), individuals with MetS have increased levels of the Gln/Glu ratio. Moreover, some researchers have suggested that Gln/Glu ratios (55, 56) are associated with MetS such as DM, CVD, and IR. In addition, in the present study, the level of Glu was higher in the MUO group than in the MHO group; however, it was not significant (Table 2). Thus, Glu, Gln, and Gln/Glu ratios are useful biomarkers of MetS in adolescents. However, Gln was significantly lower in hyperuricemia patients with MetS (57). Therefore, detailed studies and research regarding MetS and other diseases in individuals, are required in the future.
The kynurenine, Met-SO, and spermidine were significantly higher in the adolescents of the MUO group than in those of the MHO group. Some researchers reported that high levels of kynurenine are associated with obesity (58), idiopathic pulmonary arterial hypertension (59), and IR (60). Met-SO was significantly lower in patients with HTN who were on a low-sodium diet (61) and significantly higher in patients with DM (62). Thus, the results of this study suggest that kynurenine and Met-SO are associated with MetS in obese adolescents. According to Choksomngam et al. (63), in animal models, spermidine supplementation has shown to protect against diet-induced obesity. Furthermore, in humans (64) and mice (65), spermidine intake correlates with reduced blood pressure and decreased risk of CVD. In the current study, the levels of spermidine were higher in the adolescents of the MUO group than in adolescents of the MHO group. The results of this study are opposite to the results of some studies. Therefore, further studies are needed to understand the effects of spermidine in MUO and MHO in adolescents.
The results of the present study show that 2 GPLs were significantly higher in the adolescents of the MUO group than in the adolescents of the MHO group. According to Jové et al. (66), levels of GPLs were higher in the overweight and obese group with MetS than in the overweight and obese group without MetS. Furthermore, GPLs are associated with related MetS factors such as LDL-cholesterol, glucose, and IR in humans (67) and rats (68). However, for each length or double bond, the GPLs may be different in the individuals with MetS. In this study, PCaaC34:1 as a significant biomarker had significantly higher prevalence OR of MUO in adolescents as against PCaaC32:2. There is research that PCaaC34:1 reduction in type 1 DM (69), increase in Alzheimer's disease (70) and sepsis in the event of community-acquired pneumonia (69). However, there is insufficient research regarding PCaaC34:1 in individuals with MetS or obesity. Despite the need for further studies of GPLs in adolescents with MetS, the results of this study suggest that GPLs have a potential as MetS biomarkers in obese adolescents.
In particular, this study focused on two results. First, MetS associated increase in short-chain ACs in obese adolescents. Second, the correlation results of Lys (with HOMA-IR) and PCaaC34:1 (with Plt) in adolescents in the MUO group and His (with AST and ALT) correlation results in adolescents in the MHO group. This is because these results suggest the relevant MetS biomarkers in adolescents. Furthermore, studies of biomarkers as a clinical feature of MetS in obese adolescents are still limited. In addition, the TyG index also indicated a deeper relationship with the adolescents in the MUO group than the adolescents in the MHO group. This study had certain limitations. Due to the cross-sectional design of the study, it was not possible to establish a causal relationship between metabolites and MetS in adolescents. Another limitation of this study is that it was conducted with a small number of adolescents aged 14–16 years. Thus, the application of general metabolite properties for MetS obtained in the present study may be limited in adolescents of other ages, such as preschool children or adolescents aged 17 years and older. Therefore, further studies using large sample sizes are required to investigate the relationship between metabolites and MetS in adolescents.
Nevertheless, based on the results of this study, several metabolites of MetS features in obese adolescents should be considered as biomarkers. Furthermore, these metabolites and the TyG index would prove to be good biomarkers that reflect the association of MetS clinical symptoms and the presence of IR-related diseases.