*2.3. Study Outcome*

In this study, we registered the population at risk between 2009 and 2011 and analyzed the outcomes in the follow-up period from 2014 to 2017, succeeding a 2-year washout period (2012–2013). The primary endpoint of the study was newly diagnosed depression in the follow-up period. Depression was determined by a recording of international classification of diseases (ICD)-10 codes F32.0 to F34.9 on health insurance data or the taking of an antidepressant (Supplementary Tables S2 and S3). Medication status was determined by the Anatomical Therapeutic Chemical (ATC) code provided in the National Health Insurance Survey.

#### *2.4. Statistical Analysis*

The statistical significance of the general characteristics of the four groups and the mean differences in metabolic syndrome risk factor were assessed with the use of one-way analysis of variance (ANOVA). The depression incidence among the four groups was assessed and compared with the odds ratio (OR) using multiple logistic regressions by complex sampling. We applied the multivariable-adjusted proportional hazards model: model 1 adjusted for age, while model 2 adjusted for age, alcohol consumption, exercise and smoking status. We also carried out a subgroup analysis based on the sex of the participants. We also compared the OR between seven metabolic syndrome risk factors adjusted for the participant's age with the use of multiple logistic regressions.

#### **3. Results**

#### *3.1. Baseline Characteristics of the Study Population*

There were a total of 3,586,492 participants (1,936,582 men and 1,649,910 women) enrolled in this study. Tables 1 and 2 show the baseline characteristics of both the men and women participants included in the analysis by BMI categories and metabolic status. The MHN ratio in women was higher than in men (men 39.3%, women 55.2%). According to the study, 11–12% of obese participants were described as metabolically healthy, i.e., with no more than one metabolic risk factor.

**Table 1.** Characteristics of the study population at the baseline (men).


Mean ± standard deviation or proportions of participants are indicated. Abbreviations: BMI, body mass index; dBP, diastolic blood pressure; FBS, fasting blood sugar; HDL, high-density lipoprotein; MHN, metabolically healthy non-obese; MHO, metabolically healthy obese; MUN, metabolically unhealthy non-obese; MUO, metabolically unhealthy obese; sBP, systolic blood pressure; TG, triglyceride. Vigorous activity is defined as physical activity more than three times a week with a strength of moderate, severe or above.

**Table 2.** Characteristics of the study population at baseline (women).



**Table 2.** *Cont.*

Mean ± standard deviation or proportions of participants are indicated. Abbreviations: BMI, body mass index; dBP, diastolic blood pressure; FBS, fasting blood sugar; HDL, high-density lipoprotein; MHN, metabolically healthy non-obese; MHO, metabolically healthy obese; MUN, metabolically unhealthy non-obese; MUO, metabolically unhealthy obese; sBP, systolic blood pressure; TG, triglyceride. Vigorous activity is defined as physical activity more than three times a week with a strength of moderate, severe or above.

#### *3.2. Relation between Metabolically Healthy Obesity and Depression*

According to the pooled analysis for men participants with MHN as the reference category, a relationship with a higher risk of depressive symptoms was only shown in the MUO group (fully adjusted OR = 1.012; confidence interval (CI) = 1.002, 1.023) (Table 3).

**Table 3.** Odds ratio (OR) (95% CI) for the relationship between metabolic health and obesity with a risk of depression over three years of follow-up (men).


Abbreviations: CI, confidence interval; Model 1: adjustment for age; Model 2: adjustment for age, alcohol consumption, exercise and smoking status.

In female participants, however, compared to MHN as the reference category, a higher risk of depressive symptoms presented in all three other groups (Table 4). The relationship with depressive symptoms was significantly higher for MUO (fully adjusted OR = 1.096; CI = 1.085, 1.107). In comparison to all non-obese participants (MHN or MUN), the depression risk for MUO (fully adjusted OR = 1.096; CI = 1.085, 1.107) was higher than for MHO (fully adjusted OR = 1.073; CI = 1.061, 1.086). Table 4 also indicates that, in comparison to all metabolically healthy participants (MHO or MHN), the depression risk for MUO (fully adjusted OR = 1.096; CI = 1.085, 1.107) was higher than for MUN (fully adjusted OR = 1.035; CI = 1.024, 1.046).


**Table 4.** OR (95% CI) for the relationship between metabolic health and obesity with a risk of depression over three years of follow-up (women).

Abbreviations: CI, confidence interval; Model 1: adjustment for age; Model 2: adjustment for age, alcohol consumption, exercise and smoking status.

#### *3.3. Relationship between Metabolic Syndrome Factors and Depression*

Tables 5 and 6 have shown the relationship between incident depression and metabolic syndrome factors for males (Table 5) and females (Table 6). In both sexes, the conclusion was that the greater the waist circumference, the greater the frequency of depression. In male participants, fasting blood sugar is also associated with depression (fully adjusted OR = 1.001; CI = 1.001, 1.001), while, in female participants, BMI is also associated with depression (fully adjusted OR = 0.994; CI = 0.994, 0.995).

**Table 5.** Relationship between metabolic syndrome factors and incident depression (men).


Abbreviations: BMI, body mass index; CI, confidence interval; dBP, diastolic blood pressure; FBS, fasting blood sugar; HDL, high-density lipoprotein; OR, odds ratio; sBP, systolic blood pressure; TG, triglyceride. Model 1: adjustment for age; Model 2: adjustment for risk factors and age of metabolic syndrome.



Abbreviations: BMI, body mass index; CI, confidence interval; dBP, diastolic blood pressure; FBS, fasting blood sugar; HDL, high-density lipoprotein; sBP, systolic blood pressure; TG, triglyceride. Model 1: adjustment for age; Model 2: adjustment for age and risk factors of metabolic syndrome.

#### **4. Discussion**

As far as we know, this is the first Korean population-based study to depict the relevance of both depression and metabolically healthy obesity. Even though recent studies

indicate that metabolically healthy obesity (MHO) is related to an increased risk of depressive symptoms, there are still irregularities in the reports [14–16]. However, those analyses did not account for sex. In this study, we have found that the MHO group has a higher future depression risk than other subgroups in female participants, while, in male patients, there is a similar future depression risk to other subgroups.

The principal strength of this study is its nationally representative population-based study design with a huge pooled sample size. Our study is special and different from other results that can meta-analyzed based on the literature and biased by the selective publication of positive results because our current analysis was based on publicly available databases from National Health Insurance Database of Korea and not published results. It is logical to assume that the present results of these datasets generally represent Korea so they are not likely to be subject to a major publication bias.

Bi-directional associations have been outlined for the relationships between metabolic syndrome and depression, proposing that obesity, depressive symptoms and metabolic abnormalities could be associated through multiple pathways [9,19,20]. Using the NHIS-HEALS cohort, we have registered the population at risk between 2009 and 2011 and analyzed the outcomes in the follow-up period from 2014 to 2017. By excluding participants previously diagnosed with depression between 2009 and 2011, it is possible to analyze the temporal direction of the association.

In this study, complete case analysis was done by excluding participants who had one or more missing values in the MetS components (n = 9448) and whose smoking information had changed or was missing (n = 289,968). However, this study did not characterize the excluded population, which can result in bias.

The mechanisms that determine metabolically unhealthy and healthy obesity states are not popular [21,22]. One crucial factor could be where we should store the person's fat, with excess visceral fat being more harmful for metabolic health than excess subcutaneous fat [3]. Additionally, some analysis has shown that people categorized as MHO have different health characteristics to those categorized as MUO, including higher physical activity, lower smoking prevalence and higher educational levels, proposing that both behavioral and physiological factors could be involved [15]. There are also various common biological states that link metabolic factors and obesity to depression, such as impaired glycemic control, inflammation and dysregulation of the hypothalamic–pituitary–adrenocortical axis [23–28]. A different set of factors may determine the depression risk of MHO individuals from non-obese individuals, such as negative self-image, physical inactivity, functional limitations in daily life, social stigma and discrimination [29–31].

The differences in future depression between metabolically healthy obesity men and women are still not known, but there are some studies on the different effects of sex of obesity and depression. One study proposed that prenatal stress-immune programming of the different sexes effects hypothalamic-pituitary-adrenal-gonadal axes and on metabolic and cardiac functions, leading to differences between the sexes in the comorbidity of major depressive disorders and obesity/metabolic syndrome [32]. Another study has shown that obesity has a relationship with different psychosocial profiles in both men and women [33,34]. Women are associated with being overweight and having an increased risk of suicidal tendencies and clinical depression, while men are the opposite [35]. Men may favor a large muscular body rather than a skinny one and having a high body weight may not increase the risk of depression as much as being underweight. Moreover, we also noted that the greater the waist circumference, the greater the frequency of depression. However, including BMI, the incidence of depression did not affect other metabolic syndrome factors.

#### **5. Conclusions**

In conclusion, the present results from a large pooled analysis of men and women show that MUO (metabolically unhealthy obesity) has a higher risk of depressive symptoms than MHN (metabolically healthy non-obese). Furthermore, in women participants, MHO (metabolically healthy obesity) is also related to a higher risk of depressive symptoms. These findings indicate that MHO is not a totally benign condition in relation to depression in women. Therefore, reducing metabolic syndrome and obesity patients in Korea will likely reduce the incidence of depression.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/1660-460 1/18/1/63/s1, Table S1: Study population; Table S2: List of antidepressants selected in the study; Table S3: List of ICD-10 codes selected in the study.

**Author Contributions:** Y.S., J.L., D.R.K., and J.-Y.K. planned and designed the study. S.L. provided statistical assistance and prepared the figures. Y.S. and S.L. drafted the manuscript. J.-S.A., S.M., S.H., P.V. and M.-H.K. revised the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HI19C1035).

**Data Availability Statement:** The cohort profile of the NHIS-HEALS is presented elsewhere [17].

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Abbreviations**


#### **References**

