Circulating Soluble IL-6 Receptor Concentration and Visceral Adipocyte Size Are Related to Insulin Resistance in Taiwanese Adults with Morbid Obesity

Abstract

Background:

Morbid obesity is related to chronic inflammation and many metabolic complications. Interleukin (IL)-6 plays a pivotal pathophysiological role in obesity, and IL-6 trans-signaling through the soluble IL-6 receptor (sIL-6R) has a major proinflammatory effect. The aim of this study was to investigate the association between sIL-6R, adipocyte size, and insulin resistance in morbidly obese individuals.

Methods:

We measured concentrations of sIL-6R, high-sensitivity C-reactive protein, and lipid parameters and estimated homeostasis model assessment of insulin resistance (HOMA-IR) before the patients underwent bariatric surgery. Mesenteric adipose tissue was collected during surgery, and adipocyte size and concentrations of membrane-bound IL-6 receptor (mIL-6R) were evaluated. In total, 35 adults (20 men and 15 women) were recruited.

Results:

The subjects with high HOMA-IR (≥2.4) had higher fasting glucose/insulin, triglycerides, sIL-6R, and adipocyte size and lower high-density lipoprotein cholesterol and mIL-6R than those with low HOMA-IR (<2.4). Adipocyte size positively correlated with sIL-6R (r = 0.559, P = 0.001) and HOMA-IR (r = 0.773, P ≤ 0.001) independent of age, gender, body mass index (BMI), waist, and use of diabetic drugs. In addition, every 1 ng/mL increase in sIL-6R concentration corresponded to a 10.2% decrease in the likelihood of maintaining lower insulin resistance. Furthermore, an sIL-6R level of 77.45 ng/mL was a reasonable cutoff level to propose lower insulin resistance in morbidly obese subjects.

Conclusions:

Circulating sIL-6R is more closely associated with insulin resistance status than waist-to-hip ratio or BMI in morbidly obese Taiwanese adults. sIL-6R may be a useful biomarker to assess insulin resistance among morbidly obese subjects.

Introduction

A workshop held in the United States in 2014 reported that the prevalence of obesity with a rate of around 35.5% in both genders and severe obesity have continued to increase in both men and women, with rates of 4.4% and 8.1%, respectively, in 2010, accounting for around 40% of total healthcare costs for obesity.¹ In Asian populations, the risk of metabolic complications such as type 2 diabetes and dyslipidemia has increased, even with a relatively low body mass index (BMI). The International Federation for Surgery of Obesity (IFSO) stated that bariatric surgery should be considered for appropriate Asian candidates with a BMI ≥35 kg/m², regardless of whether or not they have co-morbidities.² Previous studies have reported that ∼10%–25% of individuals with obesity are metabolically healthy and that the critical difference between being metabolically healthy and unhealthy is the adipose tissue dysfunction–associated insulin resistance, which is mediated by inadequate fat differentiation and distribution.³ Therefore, investigations focusing on adipose tissue function may help to identify subjects with obesity who will benefit most from early weight loss interventions such as bariatric surgery.

The interleukin (IL)-6 system is involved in various pathophysiological processes, including glucose disposal and lipid metabolism⁴ through soluble and membrane-bound receptors.⁵ The crucial components of the IL-6 system are IL-6, soluble IL-6 receptor (sIL-6R), soluble glycoprotein 130 (sgp130), membrane-bound IL-6 receptor (mIL-6R), and membrane-bound glycoprotein 130 (gp130). mIL-6R is only expressed on hepatocytes, megakaryocytes, and some leukocytes, including monocytes, macrophages, B cells, and subtypes of T cells, whereas gp130 is diffusely present in nearly all cells. sIL-6R is almost (90%–99%) produced through proteolytic shedding of mIL-6R by a disintegrin and metalloprotease (ADAM) 10 or 17, and minor amounts (1%–10%) are generated by alternative mRNA splicing.⁵ Soluble glycoprotein 130 can neutralize the IL-6/sIL-6R complex in the circulation and is considered as a specific inhibitor of IL-6 trans-signaling.⁶

In classic IL-6 signaling, IL-6 binds to mIL-6R and then induces homodimerization of gp130 to form a high-affinity hexamer complex of two IL-6, two IL-6R, and two gp130 subunits. The hexamer complex is necessary for inducing downstream signaling. So, classic IL-6 signaling is limited to mIL-6R holding cells, whereas in IL-6 trans-signaling, circulating sIL-6R can also comparably bind to IL-6, then further forming hexamer complex with gp130 to induce downstream signaling, which is not limited to mIL-6R holding cells. Pro- and anti-inflammatory properties of IL-6 are balanced by a trend toward IL-6 trans-signaling or classic signaling, respectively. In general, IL-6 classic signaling possesses anti-inflammatory effects such as antibacterial infections⁷ and regeneration of intestinal epithelial cells,⁸ whereas IL-6 trans-signaling possesses proinflammatory effects such as stimulation of endothelial cells by recruiting monocytes,⁹ enhancing Th17 cell differentiation by suppressing regulatory T cells.¹⁰

The IL-6 system also plays a role as a major inflammatory mediator in chronic obesity.¹¹ Clinical studies have shown that individuals with obesity have elevated IL-6 concentrations,¹² and significant decreases in IL-6 concentrations have been reported after bariatric surgery.¹³ In comparison, results of investigations on direct correlations between IL-6 and insulin resistance have been inconsistent.^14
–16 Furthermore, specific assessments on the natural inhibitor of IL-6 trans-signaling, sgp130, have disclosed that it is significantly associated with metabolic syndrome^17,18 and polycystic ovary syndrome.¹⁹ However, the role of the direct agonist of IL-6 trans-signaling, sIL-6R, is still unclear. Therefore, in this study, we aimed to evaluate the concentrations of circulating sIL-6R and collect mesenteric adipose tissue to measure mIL-6R and adipocyte size in patients with morbid obesity to clarify the association between sIL-6R, mIL-6R, visceral adipocyte size, and insulin resistance.

Materials and Methods

In total, 35 adults (20 males and 15 females) who received bariatric surgery were recruited from the Tri-Service General Hospital and Taipei Medical University Hospital. The criteria for inclusion into this trial were as follows: age 25–60 years, BMI ≥35 kg/m², absence of infection within the previous 3 weeks, and no history of malignant tumors. The exclusion criteria were pregnancy, current or a history of cerebrovascular accident, myocardial infarction, heart failure, renal failure, hepatic failure, autoimmune disorders, endocrine diseases, or psychiatric diseases, including mood disorders and alcoholism. All participants provided written informed consent and agreed to the use of blood and tissue samples in this study. The institutional review boards of our hospitals approved this study (Number: TSGH10208).

Anthropometric measurements

Body weight, body height, waist circumference, and hip circumference were measured to the nearest 0.1 cm, and the waist-to-hip circumference ratio and BMI were calculated. Body weight was measured barefoot with the patients wearing light indoor clothing. Waist circumference was measured at the midway horizontal plane between the inferior margin of the last rib and the crest of the ilium. Hip circumference was measured at its widest point. BMI was calculated as weight in kilograms divided by the square of height in meters. Blood pressure was measured from the right arm in a sitting position after resting for 5 min. One minute later, blood pressure was measured again and the average value was used in the analysis.

Biochemical variable measurement

Venous blood samples were drawn following a 10-hr fast. Concentrations of glucose, insulin, lipids, and inflammatory cytokines, including high-sensitivity C-reactive protein (hs-CRP) and sIL-6R, were then measured. Serum concentrations of total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, and hs-CRP were measured using a Beckman Synchron LX20 analyzer (LX20; Beckman Coulter, Brea, CA). Plasma glucose concentrations were determined using the glucose oxidase method on a Beckman Glucose Analyzer II (Beckman Instruments, Fullerton, CA). Plasma insulin concentrations were measured using a commercially available immunoradiometric kit (BioSource Europe S.A., Nivelles, Belgium). The intra-assay and interassay coefficients of variance for the insulin measurements were 2.2% and 6.5%, respectively. Serum sIL-6R was assessed using a Gen-Probe Diaclone enzyme-linked immunosorbent assay kit (Cat. No: 850.510.096). Insulin resistance was assessed using the homeostasis model assessment (HOMA), in which the homeostasis model assessment of insulin resistance (HOMA-IR) = [fasting insulin (mU/L)] × [fasting glucose (mmol/L)]/22.5.²⁰ HOMA-IR values of 2.2–2.5 were considered as the first cutoff in the Korea National Health and Nutrition Examination Survey.²¹ Therefore, we used the HOMA-IR value of 2.4 to differentiate insulin resistance status in this study.

Adipose tissue analysis

Around 20 grams of mesenteric adipose tissues was collected during bariatric surgery. The tissue samples were preserved in 60 mL Dulbecco's modified Eagle's medium and transferred to the laboratory within 1 hr while being kept at 4°C. Concentrations of mIL-6R were assessed using a Gen-Probe Diaclone enzyme-linked immunosorbent assay kit (Cat. No: 850.510.096) in culture medium. Adipose tissues were further fixed in formalin, embedded in paraffin, and sliced to 5 μm thickness. Immunohistochemical staining was then performed, and all sections were counterstained with hematoxylin. Adipocyte size was evaluated by averaging the cross-sectional area of the five largest adipocytes in each of 10 randomly selected 100× magnification fields using ImageJ software (version 1.44p; National Institutes of Health, MD).

Statistical analyses

Continuous variables were assessed using the Mann–Whiney U test and presented as median values with quartiles. Categorical variables were assessed using the chi-squared test and presented as percentages. A P value of less than 0.05 was considered statistically significant. Relationships between adipocyte size and other variables were analyzed using Spearman rank order correlations and partial correlation analysis after adjusting for age, gender, BMI, waist circumference, and the use of diabetic drugs. Associations between IL-6 receptors and adipocyte size in the patients with the lowest and highest HOMA-IR values and those with diabetes were evaluated by Kruskal–Wallis one-way ANOVA with pairwise comparisons. Multivariate logistic regression analysis with the HOMA-IR <2.4 group as the dependent variable was performed to identify the independent determinants of gender, age, BMI, waist-to-hip ratio, sIL-6R, and mIL-6R, then backward LR stepwise logistic regression was further applied. Receiver operating characteristic curves with the HOMA-IR <2.4 group as the state variable and sIL-6R as the test variable were analyzed. All statistical analyses were performed using SPSS software, version 22 (IBM, Chicago, IL).

Results

Comparisons of anthropometric variables and biochemical characteristics stratified by HOMA-IR are shown in Table 1. Fasting glucose, fasting insulin, triglycerides, sIL-6R, and adipocyte size were significantly higher in the HOMA-IR ≥2.4 group than in the HOMA-IR <2.4 group, and the high HOMA-IR group had a higher prevalence of diabetes and male subjects. In contrast, HDL cholesterol and mIL-6R concentrations were significantly lower in the HOMA-IR ≥2.4 group than in the HOMA-IR <2.4 group. Of note, there were no significant differences in anthropometric characteristics, including body weight, BMI, waist circumference, or waist-to-hip ratio, between the two groups despite significant differences in HOMA-IR.

Table 1.

Baseline Anthropometric and Biochemical Characteristics of the Study Population

	HOMA-IR <2.4 (n = 15)	HOMA-IR ≥2.4 (n = 20)	P
Gender (male), %	33.3	75	0.014^*
Diabetes, %	0	50	0.002^*
Age (years)	38 [32; 47]	32.2 [35.5; 41.2]	0.676
BH (cm)	165 [162; 168]	170 [162.2; 173.7]	0.300
BW (kg)	107.9 [100.6; 113.5]	113.9 [104.3; 137.2]	0.121
BMI (kg/m²)	40.1 [37.2; 41.5]	41.3 [36.5; 45.5]	0.317
Waist (cm)	116 [113; 121]	123 [112.5; 135.7]	0.182
Hip (cm)	124 [117.5; 130.5]	122.2 [116.7; 135]	0.881
Waist-to-hip ratio	0.98 [0.88; 1.03]	0.98 [0.95; 1.03]	0.325
Systolic BP (mmHg)	133 [119; 150]	136 [124.5; 156]	0.617
Diastolic BP (mmHg)	86 [74; 105]	86 [79.5; 95.7]	0.907
Fasting glucose (mmol/L)	4.83 [4.61; 6.22]	6.05 [5.11; 8.57]	0.022^*
Fasting insulin (pmol/L)	25.0 [17.4; 50.0]	136.8 [80.6; 164.6]	<0.001^**
HOMA-IR	0.88 [0.61; 1.91]	4.63 [3.39; 7.31]	<0.001^**
Triglycerides (mmol/L)	1.33 [1.18; 2.24]	2.07 [1.59; 3.16]	0.023^*
HDL cholesterol (mmol/L)	1.06 [0.93; 1.22]	0.90 [0.86; 1.05]	0.019^*
Total cholesterol (mmol/L)	4.56 [3.57; 5.44]	4.65 [3.82; 5.01]	0.714
LDL cholesterol (mmol/L)	2.95 [2.15; 3.44]	2.92 [2.24; 3.21]	0.751
hs-CRP (mg/L)	0.72 [0.37; 0.91]	0.45 [0.22; 0.70]	0.395
sIL-6R (ng/mL)	61.4 [54.2; 76.2]	81.9 [77.1; 101.9]	<0.001^**
mIL-6R (ng/mL)	35.6 [25.1; 51.5]	26.2 [18.7; 35.8]	0.049^*
Adipocyte size (kμm²)	50.26 [46.25; 53.26]	65.52 [60.62; 81.85]	<0.001^**

Continuous variables were analyzed using the Mann–Whitney U test and are presented as median values and [quartiles]; categorical variables were analyzed using the chi-squared test and are presented as percentages.

P < 0.05; ^** P < 0.001.

BH, body height; BMI, body mass index; BP, blood pressure; BW, body weight; DM, diabetes mellitus; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment of insulin resistance; hs-CRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; mIL-6R, membrane-bound interleukin 6 receptor; sIL-6R, soluble interleukin 6 receptor.

In Table 2, the visceral adipocyte size was significantly positively correlated with sIL-6R (r = 0.631, P < 0.001), HOMA-IR (r = 0.943, P < 0.001), and triglycerides (r = 0.448, P = 0.007) and inversely correlated with HDL cholesterol (r = −0.353, P = 0.037). However, the relationship with lipid parameters disappeared after adjusting for age, gender, BMI, waist circumference, and use of diabetic drugs. Of note, HOMA-IR and sIL-6R were still strongly correlated with adipocyte size after adjustments (r = 0.773, P < 0.001, and r = 0.559, P < 0.001, respectively). Adipocyte size also had a negative trend of correlation with mIL-6R, although this did not reach statistical significance. No significant direct correlation was observed between adipocyte size and major anthropometric characteristics such as BMI, waist circumference, and waist-to-hip ratio.

Table 2.

Spearman Correlation Coefficients Between Adipocyte Size, Lipid Profile, hs-CRP, sIL-6R, mIL-6R, and HOMA-IR in Subjects with Morbid Obesity

	Adipocyte size
	Model 1 ^a		Model 2 ^b
	r^a	P	r^b	P
Triglycerides	0.448	0.007^*	0.227	0.228
HDL cholesterol	−0.353	0.037^*	−0.070	0.712
Total cholesterol	−0.026	0.883	−0.061	0.751
LDL cholesterol	−0.143	0.413	−0.151	0.427
hs-CRP	−0.157	0.369	0.196	0.299
sIL-6R	0.631	<0.001^**	0.559	0.001^*
mIL-6R	−0.311	0.069	−0.219	0.246
HOMA-IR	0.943	<0.001^**	0.773	<0.001^**

A direct correlation between adipocyte size and other variables.

Adjusting for age, gender, BMI, waist circumference, and use of diabetic drugs.

P < 0.05; ^** P < 0.001.

We further stratified the patients into three groups, HOMA-IR <2.4, HOMA-IR ≥2.4, and those with diabetes, to evaluate the differences of sIL-6R and mIL-6R and adipocyte size. Pairwise comparisons (Table 3) showed that both sIL-6R and adipocyte size were significantly different in patients with diabetes versus those with HOMA-IR <2.4 (P = 0.012 and P < 0.001, respectively) and in those with HOMA-IR ≥2.4 versus HOMA-IR <2.4 (P = 0.005 and P < 0.001, respectively), but not in those with diabetes versus HOMA-IR ≥2.4. There were no significant differences in mIL-6R between these three groups.

Table 3.

Analysis of Interleukin 6 Receptors and Adipocyte Size Among Those with Low and High HOMA-IR and Those with Diabetes

	HOMA-IR <2.4 (n = 15)	HOMA-IR ≥2.4 (n = 10)	Diabetes (n = 10)	p^a	p^b	p^c
sIL-6R (ng/mL)	61.4 [54.2; 76.2]	80.3 [78; 90.9]	88.8 [67.4; 108.3]	0.005^*	0.012^*	1.000
mIL-6R (ng/mL)^d	35.6 [25.1; 51.5]	32.7 [16.7; 37.3]	23.6 [18.6; 26.3]	—	—	—
Adipocyte size (kμm²)	50.26 [46.25; 53.26]	65.52 [62.33; 79.65]	70.37 [60.45; 85.48]	<0.001^**	<0.001^**	1.000

Data were analyzed using Kruskal–Wallis one-way ANOVA with pairwise comparisons and are expressed as median values and [quartiles].

HOMA-IR ≥2.4 vs. HOMA-IR <2.4.

Diabetes vs. HOMA-IR <2.4.

Diabetes vs. HOMA-IR ≥2.4.

Multiple comparisons were not performed because the overall test did not show significant differences across samples.

P < 0.05; ^** P < 0.001.

We then preformed multiple and stepwise logistic regression analyses to assess whether gender, age, BMI, waist-to-hip ratio, sIL-6R, and mIL-6R were potential associated factors of lower insulin resistance. As seen in Table 4, only gender and sIL-6R were considered as associated factors (P = 0.018 and P = 0.016, respectively) and age, BMI, waist-to-hip ratio, and mIL-6R did not significantly associate with insulin resistance status. Male gender and each 1 ng/mL increase in sIL-6R concentration significantly decreased the likelihood (93.8% and 10.2%, respectively) of maintaining lower insulin resistance in those with morbid obesity. Moreover, receiver operating characteristic curve analysis showed that sIL-6R significantly proposed lower insulin resistance (P < 0.001) with an area under the curve of 0.86 (Fig. 1). We finally assessed the best cutoff value based on maximum sensitivity plus specificity, and the sIL-6R level of 77.45 ng/mL was considered to be optimal to propose lower insulin resistance in adult Taiwanese patients with morbid obesity, which possessed 86.7% sensitivity and 75% specificity.

FIG. 1.

ROC curve of soluble IL-6 receptor for proposing lower insulin resistance (HOMA-IR <2.4) in morbidly obese subjects. A cutoff level of 77.45 ng/mL was identified with maximum sensitivity and specificity (sensitivity: 0.867, specificity: 0.75). HOMA-IR, homeostasis model assessment of insulin resistance; IL, interleukin.

Table 4.

Multivariate Logistic Regression Analysis on Lower Insulin Resistance (HOMA-IR <2.4) in Subjects with Morbid Obesity

	Variables ^a	Odds ratio	P	95% CI
Model 1	Gender (male)	0.044	0.045^*	0.002–0.934
	Age (years)	1.062	0.522	0.884–1.274
	BMI (kg/m²)	0.867	0.350	0.642–1.170
	WHR	44.05	0.723	0.000–53.93
	sIL-6R (ng/mL)	0.894	0.025^*	0.810–0.986
	mIL-6R (ng/mL)	1.038	0.481	0.936–1.152
Model 2^b
Step1	Gender (male)	0.059	0.029^*	0.005–0.752
	Age (years)	1.060	0.537	0.882–1.274
	BMI (kg/m²)	0.888	0.370	0.684–1.152
	sIL-6R (ng/mL)	0.892	0.024^*	0.807–0.985
	mIL-6R (ng/mL)	1.035	0.491	0.938–1.143
Step2	Gender (male)	0.067	0.024^*	0.006–0.695
	BMI (kg/m²)	0.891	0.396	0.682–1.164
	sIL-6R (ng/mL)	0.900	0.018^*	0.824–0.982
	mIL-6R (ng/mL)	1.028	0.413	0.963–1.097
Step3	Gender (male)	0.062	0.018^*	0.006–0.615
	sIL-6R (ng/mL)	0.898	0.016^*	0.823–0.981
	mIL-6R (ng/mL)	1.027	0.313	0.975–1.082

Gender, age, BMI, WHR, sIL-6R, and mIL-6R were assessed using multivariate logistic regression.

Gender, age, BMI, WHR, sIL-6R, and mIL-6R were further assessed using backward LR stepwise multivariate logistic regression.

P < 0.05.

WHR, waist-to-hip ratio.

Discussion

We found that the patients in the HOMA-IR ≥2.4 group had both increased concentrations of serum sIL-6R and decreased concentrations of mIL-6R in visceral adipose tissue. This could be explained by the increased activity of ADAMs with regard to lipotoxicity and glucotoxicity.²² Then, activated ADAMs could enhance shedding of mIL-6R from infiltrated macrophages within the hypertrophic adipose tissue. However, further investigations are needed to directly evaluate the activity of ADAMs in visceral adipose tissue of individuals with obesity. In addition, adipocyte size was strongly correlated with serum concentrations of sIL-6R and HOMA-IR independently of anthropometric characteristics, and there were no significant differences in anthropometric characteristics between the high and low HOMA-IR groups. These results suggest that there may be interaction between adipose differentiation, IL-6 trans-signaling, and insulin resistance, whereas anthropometric characteristics do not play a role to adequately assess adipose tissue function in patients with morbid obesity. Furthermore, our results demonstrated that serum sIL-6R concentrations and adipocyte size were significantly higher in the high HOMA-IR and diabetes groups compared with the low HOMA-IR group. The potential mechanism could be that adipocyte hypertrophy caused hypoxia in adipose tissue, then upregulated proinflammatory cytokines,²³ which ultimately results in chronic inflammation and the development of systemic insulin resistance. In addition, we found that circulating sIL-6R as a direct agonist of IL-6 trans-signaling could be a potential biomarker to evaluate the status of insulin resistance in individuals with morbid obesity. However, more specific investigations with a larger number of patients and long-term follow-up are needed to clarify clinical usefulness.

Studies focusing on the IL-6 system have reported that IL-6 serum concentrations change dramatically during a pathological course²⁴ with inconsistent associations with metabolic processes,²⁵ whereas sIL-6R and sgp130 concentrations fluctuate less in blood with a more accurate connection with the IL-6 system pathway. sIL-6R has been found to represent IL-6 trans-signaling in many detrimental processes of different diseases, and it is well known that concentrations of sIL-6R are increased in patients with rheumatoid arthritis²⁶ and sepsis.²⁷ On the other hand, IL-6 trans-signaling may possess beneficial effects in specific conditions, such as buffering elevated IL-6 in blood through formation of the IL-6/sIL-6R complex, then being rapidly neutralized by sgp130²⁸ to eliminate acute inflammatory reactions.

Currently, only few clinical studies have evaluated the link between sIL-6R and insulin resistance in metabolic diseases. In 2004, Abbatecola²⁹ found an inverse correlation between HOMA and sIL-6R in nondiabetic subjects, but this study included subjects with age ranging from 22 to 104 years and the negative correlation seemed driven by the elder people. Furthermore, in 2010, Zuliani et al.¹⁷ revealed a trend toward raised concentrations of sIL-6R in elder subjects with metabolic syndrome. Two studies that focused on children also showed contradicting results. One study supported elevated sIL-6R concentrations in overweight Mexican American children,³⁰ whereas another report showed decreased sIL-6R concentrations in obese children and adolescents.³¹ In 2010, Nikolajuk et al.¹⁹ disclosed that women with polycystic ovary syndrome had lower concentrations of sIL-6R. This result is incompatible to our finding, but a possible explanation may be that women with polycystic ovary syndrome are under chronic estrogen exposure and progesterone resistance due to ovarian dysfunction,³² and an elevated level of estrogen has been correlated with lower serum concentrations of sIL-6R.³³ In 2013, Weiss et al.¹⁸ reported that sIL-6R was significantly elevated in patients with metabolic syndrome, along with a partial association with endothelial dysfunction and arterial stiffness. Based on these reports, the association between sIL-6R and insulin resistance was still unclear and inconsistent in different population subgroups. Therefore, we enrolled people under extreme metabolic status of morbid obesity. To our knowledge, this is the first study to evaluate the IL-6 trans-signaling in morbidly obese subjects. Our results showed that sIL-6R was significantly increased in groups with high HOMA-IR and diabetes, which supports the finding that IL-6 trans-signaling can play a role in proinflammatory activities in individuals with obesity and contribute to insulin resistance.

Our results highlight the roles of sIL-6R and adipocyte size in obesity-derived insulin resistance, which has rarely been reported in the literature. However, there are several limitations to this study. First, we only recruited a small number of subjects with morbid obesity in this cross-sectional study, and further studies with more patients are needed to verify our preliminary findings. Second, we did not directly measure the total body fat mass, visceral fat mass, or subcutaneous fat mass. Therefore, we could not evaluate the distribution of adipose tissue.

In conclusion, our results showed that mesenteric adipocyte size and circulating sIL-6R concentrations were significantly increased in metabolically unhealthy patients with morbid obesity, independently of BMI, waist circumference, and waist-to-hip ratio. In addition, adipose tissue dysfunction was independently highly correlated with sIL-6R and HOMA-IR, and sIL-6R was a suitable associated factor for the severity of insulin resistance in our study population. Therefore, sIL-6R may be a suitable biomarker to evaluate the metabolic status in subjects with morbid obesity. Understanding the interaction between components of the IL-6 system, macrophages and adipose tissue may help in the development of therapeutic applications in patients with obesity-related metabolic and inflammatory diseases.

Footnotes

Acknowledgments

This work was supported by research grants from the National Science Council (NSC 100-2314-B-016-026-MY3, NSC101-2314-B-016-032, NSC102-2314-B-016-007-MY2, NSC102-2314-B-016-044-MY2), National Defense Medical Center (MAB-104-82), and Tri-Service General Hospital (TSGH-C103-007-S03, TSGH-C104-007-S03, TSGH-C103-007-S04, TSGH-C104-007-S04, TSGH-C104-176, TSGH-C104-197, TSGH-C104-198, TSGH-C104-199) and partial support by the grant of MOHW10350, Taiwan.

Author Disclosure Statement

No conflicting financial interests exist.

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