Cross-regulation between adipose tissue innervation and metaflammation: a potential therapeutic target for obesity

Obesity, marked by adipose tissue dysfunction and systemic metaflammation, poses a major global health burden. Emerging evidence underscores a critical interplay between neural regulation and immune-metabolic crosstalk in obesity pathogenesis. This review highlights the dynamic roles of sympathetic and sensory nerves in lipid metabolism, as well as metaflammation involving macrophage polarization, inflammatory cytokine cascades, and mitochondrial dysfunction. In obesity, decreased sympathetic nerve density and impaired adrenergic receptor signaling compromise lipolysis and thermogenesis, while sensory neuropeptides worsen metabolic dysregulation through immune cell interactions. Adipose tissue macrophages adopt pro-inflammatory phenotypes, releasing cytokines that inhibit insulin signaling - forming pathological crown-like structures. Mitochondrial dysfunction, characterized by excessive fission and reduced fusion, disrupts energy homeostasis and increases oxidative stress. Therapeutic approaches targeting neuropeptide signaling, inflammasome activation, and mitochondrial dynamics show promise in restoring metabolic balance. The neuro-immune-metabolic axis thus represents a novel therapeutic frontier for obesity, supporting integrated strategies targeting neural, inflammatory, and mitochondrial pathways.