Adiponectin Signaling as an Immunometabolic Regulator in COVID-19: Mechanistic Insights and Therapeutic Potential

BACKGROUND: Adiponectin is a pleiotropic adipocytokine with anti-inflammatory, antioxidant, and insulin-sensitizing functions. Its regulatory role in glucose and lipid metabolism, endothelial homeostasis, and immune responses positions it as a key determinant of immunometabolic resilience. Dysregulated adiponectin signaling has been increasingly implicated in adverse COVID-19 outcomes, particularly among individuals with metabolic comorbidities. OBJECTIVE: To synthesize mechanistic, preclinical, and translational evidence on adiponectin signaling in COVID-19 and evaluate its potential as a therapeutic and lifestyle-modulated target. METHODS: A critical review of published literature on adiponectin biology, AdipoR1/R2 receptor signaling, AMPK and PPAR-α pathways, cytokine regulation, oxidative stress, and infection-induced metabolic reprogramming was conducted. RESULTS: COVID-19 is consistently associated with reduced circulating adiponectin, with the greatest declines observed in obesity, diabetes, and metabolic syndrome. Mechanistic and animal studies show that adiponectin activation attenuates hyperinflammation, oxidative stress, endothelial dysfunction, and multi-organ injury. These effects are mediated through AMPK activation, PPAR-α modulation, NF-κB suppression, and restoration of metabolic-immune balance. CONCLUSIONS: Adiponectin signaling represents a promising therapeutic target for mitigating COVID-19 severity, especially in metabolically vulnerable populations. Pharmacological agonists and lifestyle interventions that enhance adiponectin pathways warrant further translational investigation.