Interleukin-6 Mediated Metabolic Regulation in Obesity

Interleukin-6 (IL-6) occupies a central yet paradoxical position in the metabolic landscape of obesity. Originally characterised as a pro-inflammatory cytokine, IL-6 has since been recognised for its direct actions on adipocytes, hepatocytes and immune cells, influencing lipolysis, thermogenesis and insulin sensitivity. In obesity, chronically elevated IL-6 contributes to low-grade inflammation and insulin resistance through induction of suppressors of cytokine signalling and recruitment of inflammatory macrophages. Paradoxically, acute IL-6 pulses can promote energy expenditure by enhancing mitochondrial function and thermogenic gene expression in brown and beige adipocytes. Tissue-specific modes of IL-6 signalling – classical receptor engagement in metabolic cells and trans-signalling via the soluble IL-6 receptor in immune populations – underlie diverse outcomes, from adipose tissue inflammation to adaptive thermogenesis. Understanding this dual nature is essential for harnessing IL-6 pathways to treat obesity and its metabolic complications.

Research from Nature Portfolio

Recent studies have elucidated cell-type-specific IL-6 networks in diet-induced obesity. Investigation of bone-marrow-derived grancalcin revealed its accumulation in obesity and capacity to bind adipocyte prohibitin-2, triggering PAK1–NF-κB signalling, adipose inflammation and insulin resistance; neutralising grancalcin improved metabolic parameters in obese mice. Complementary work on T-cell IL-6 receptor deficiency demonstrated that classical IL-6 signalling in T lymphocytes drives early adipose inflammation and insulin resistance during high-fat feeding, whereas prolonged obesity shifts to trans-signalling-dominated responses. Together, these findings refine our understanding of IL-6’s context-dependent roles in adipose tissue and immune crosstalk.

Interleukin-6 Mediated Metabolic Regulation in Obesity publication trend

The graph below shows the total number of articles in interleukin-6 mediated metabolic regulation in obesity across all publications each year (not limited to Nature Index journals).

Technical terms

Interleukin-6 (IL-6): A cytokine that modulates immune responses and directly influences metabolic pathways in liver and adipose tissue.

Classical signalling: IL-6 binding to membrane-bound IL-6 receptor and gp130 co-receptor, primarily in hepatocytes and adipocytes.

Trans-signalling: IL-6 association with soluble IL-6 receptor, enabling activation of gp130 on cells lacking the membrane receptor, notably immune cells.

Thermogenesis: Heat production in brown and beige adipocytes driven by uncoupling protein activity, contributing to increased energy expenditure.

Lipolysis: Enzymatic breakdown of triglycerides into free fatty acids and glycerol within adipocytes, regulating fat storage and mobilization.

References

1. Myeloid-derived grancalcin instigates obesity-induced insulin resistance and metabolic inflammation in male mice. Nature Communications (2024).
2. Interleukin-6: An Under-Appreciated Inducer of Thermogenic Adipocyte Differentiation. International Journal of Molecular Sciences (2024).
3. Interleukin-6 promotes visceral adipose tissue accumulation during aging via inhibiting fat lipolysis. International Immunopharmacology (2024).
4. Blocking IL-6 trans-Signaling Prevents High-Fat Diet-Induced Adipose Tissue Macrophage Recruitment but Does Not Improve Insulin Resistance. Cell Metabolism (2015).
5. Suppressor of Cytokine Signaling-3 (SOCS-3), a Potential Mediator of Interleukin-6-dependent Insulin Resistance in Hepatocytes*. Journal of Biological Chemistry (2003).
6. Temporal and tissue-specific requirements for T-lymphocyte IL-6 signalling in obesity-associated inflammation and insulin resistance. Nature Communications (2017).