Inflammatory Mechanisms in Metabolic Disorders

Chronic low-grade inflammation is a hallmark of metabolic disorders such as obesity, type 2 diabetes and non-alcoholic fatty liver disease. Excess nutrients and lipid accumulation trigger activation of innate immune cells, particularly macrophages, within metabolically active tissues including adipose, liver and muscle. This immune activation leads to the secretion of proinflammatory cytokines and adipokines that interfere with insulin signalling through kinases such as JNK and IKKβ and transcriptional regulators such as NF-κB. In adipose tissue, macrophage polarization shifts towards a proinflammatory M1 phenotype, exacerbating tissue dysfunction and insulin resistance. The NLRP3 inflammasome and other pattern recognition receptors detect metabolic stress signals to amplify cytokine release. Cross-talk between immune cells and parenchymal cells is mediated by extracellular vesicles, hepatokines and bioactive lipids, further disrupting systemic energy homeostasis. Recent insights highlight the role of adipose-tissue browning and mitochondrial UCP1 expression in mitigating inflammation, while enhanced clearance of proinflammatory exosomes offers therapeutic promise. Understanding these intertwined pathways is essential for developing targeted interventions that restore metabolic balance and alleviate the global burden of metabolic disease.

Research from Nature Portfolio

Recent studies have identified a liver-derived serine protease inhibitor that modulates adipose tissue function. Elevated hepatic expression of this factor during recovery from lipodystrophy promotes the proliferation of white and brown preadipocytes and upregulates mitochondrial UCP1 in mature adipocytes, driving browning of fat depots. Transgenic overexpression in murine models enhances energy expenditure, reduces adiposity and improves systemic glucose tolerance, whereas genetic deletion impairs mitochondrial activity and exacerbates insulin resistance. Mechanistically, this hepatokine forms a complex with an Eph receptor on adipocytes to regulate downstream signalling pathways. The findings reveal a direct endocrine link between hepatic signals and adipose-immune cross-talk, offering a novel angle on how organ-derived factors can attenuate inflammation and restore metabolic homeostasis.

Inflammatory Mechanisms in Metabolic Disorders publication trend

The graph below shows the total number of articles in inflammatory mechanisms in metabolic disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Adipokine: A signalling molecule secreted by adipose tissue influencing immune and metabolic pathways.

Cytokine: A small protein released by immune cells to modulate inflammation and cell communication.

Inflammasome: A multiprotein complex within immune cells that activates inflammatory cytokines in response to stress.

Macrophage polarization: The spectrum of activation states from proinflammatory (M1) to anti-inflammatory (M2) in macrophages.

Hepatokine: A bioactive protein secreted by the liver that affects the metabolism of distant organs.

Exosome: A small extracellular vesicle that carries proteins, lipids and nucleic acids between cells.

References

1. The immunology of sickness metabolism. Cellular & Molecular Immunology (2024).
2. Hepatic SerpinA1 improves energy and glucose metabolism through regulation of preadipocyte proliferation and UCP1 expression. Nature Communications (2024).
3. Blocking the SIRPα-CD47 axis promotes macrophage phagocytosis of exosomes derived from visceral adipose tissue and improves inflammation and metabolism in mice. Journal of Biomedical Science (2025).