What is the clinical significance of interleukin‑6 in obesity and its role as a biomarker?

Interleukin-6 in Obesity: Clinical Significance and Biomarker Role

Interleukin-6 (IL-6) is a key inflammatory biomarker in obesity that reflects chronic low-grade inflammation, correlates with visceral adiposity and insulin resistance, and serves as a modifiable marker of cardiovascular risk—though it does not provide additional predictive power beyond C-reactive protein (CRP) for clinical decision-making. 1

IL-6 as a Marker of Obesity-Related Inflammation

Source and Pathophysiology

• Adipose tissue, particularly visceral fat, is a major source of IL-6 production in obesity, with adipocytes and adipose tissue macrophages both contributing to elevated systemic levels 1, 2
• IL-6 acts directly at the insulin receptor to decrease receptor signaling and increase insulin resistance, making it a mechanistic link between obesity and metabolic dysfunction 1, 3
• The cytokine mediates lipolysis indirectly and augments hepatic synthesis of fatty acids, thereby increasing serum levels of free fatty acids and triglycerides 1

Relationship with Adiposity

• IL-6 levels are positively correlated with the degree of obesity, visceral fat accumulation, and body mass index (BMI) across all age groups 1, 4
• In adolescents with metabolic syndrome, elevated IL-6 levels are observed, but this relationship disappears after adjustment for abdominal obesity—indicating that adiposity is the primary driver 1
• Waist circumference and visceral fat are independent predictors of IL-6 elevation, with fat distribution being more important than total body fat 3

Clinical Utility as a Biomarker

Predictive Value Limitations

• IL-6 does not supply additional predictive power for cardiovascular disease beyond CRP and TNF-α, limiting its standalone clinical utility 1
• While IL-6 is associated with cardiovascular risk factors including insulin resistance, dyslipidemia, and blood pressure, CRP remains the preferred inflammatory marker for risk stratification 1

Response to Interventions

• Weight reduction through dietary restriction and increased physical activity produces significant reductions in IL-6 levels in both children and adolescents 1
• In obese children followed for 9 months, those with decreased BMI z-scores demonstrated parallel decreases in both IL-6 and CRP 1
• IL-6 concentrations increase acutely in response to exercise but decrease chronically with sustained improvements in body composition 1

Age and Sex Considerations

Pediatric Populations

• IL-6 levels are paradoxically higher in healthy children than in adults, and these levels decrease with increasing age—in contrast to CRP, which rises with age 1
• In juveniles specifically, leptin is the best predictor of IL-6 plasma levels, suggesting an important role for this adipokine in initiating obesity-related inflammation 4
• Caution is required when interpreting IL-6 levels in childhood due to age-related variations and limited normative data 1

Sex Differences

• Sex-related differences in inflammatory markers exist in postpubertal children, though specific IL-6 differences are less well characterized than for adhesion molecules 1

Mechanistic Insights

Signaling Pathways

• IL-6 can activate cells through two receptor constellations: classic signaling (membrane-bound IL-6R) and trans-signaling (soluble IL-6R), with the source of IL-6 production determining the physiological effects 5
• IL-6 derived from adipocytes increases macrophage infiltration of adipose tissue through trans-signaling, while IL-6 from myeloid cells suppresses infiltration through canonical signaling 5
• The ADAM10/17 metalloprotease promotes trans-signaling by generating soluble IL-6 receptor α, switching IL-6 from anti-inflammatory to pro-inflammatory effects 5

Genetic Variability

• IL-6 gene haplotypes are significantly associated with waist circumference and BMI, with certain variants (particularly rs2069827) consistently linked to higher adiposity measures 6
• The commonly studied -174G>C polymorphism shows minimal association with adiposity in meta-analyses of nearly 27,000 individuals 6

Common Pitfalls and Clinical Caveats

Interpretation Challenges

• Do not use IL-6 as a standalone biomarker for cardiovascular risk stratification—CRP provides equivalent or superior predictive value with better standardization 1
• Recognize that the relationship between IL-6 and metabolic syndrome is largely mediated by abdominal obesity, not independent of it 1
• Acute exercise transiently increases IL-6 (as a myokine with beneficial effects), which should not be confused with chronic elevation from adipose tissue 1

Clinical Application

• Weight loss remains the single most effective intervention to reduce IL-6 levels and improve associated metabolic dysfunction 7
• IL-6 measurement may be useful for monitoring response to weight loss interventions in research settings, but routine clinical measurement is not recommended given lack of additional predictive power 1
• The inflammatory cascade triggered by IL-6 is further enhanced by hyperinsulinemia, creating a vicious cycle that requires addressing both obesity and insulin resistance 1