Adiponectin ameliorates chronic-intermittent-hypoxia-induced insulin resistance by modulating macrophage inflammation in visceral white adipose tissue.

BACKGROUND

Chronic intermittent hypoxia (CIH) is a key pathogenic mechanism of obstructive sleep apnea (OSA). OSA is an independent risk factor for insulin resistance (IR) in non-obese individuals, yet its underlying mechanisms remain unclear. Dysfunctional visceral adipose tissue (vWAT) is a central driver of insulin resistance and is closely associated with IR. Adiponectin (Ad), secreted by adipose tissue, plays a crucial role in metabolic regulation through insulin sensitization and anti-inflammatory effects. This study investigates how CIH induces IR and how Ad alleviates this effect by modulating macrophage polarization in visceral white adipose tissue (vWAT).

METHODS

This study successfully established a lean murine CIH-IR model. C57BL/6J mice were divided into three groups: standard control (NC), CIH, and CIH supplemented with Ad (CIH + Ad), with 10 mice in each group. We evaluated systemic glucose homeostasis using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index and assessed macrophage infiltration in the white adipose tissue of both epididymides (eWAT) through immunofluorescence (IF) staining, flow cytometry, and ELISA. Additionally, we further investigated these pathways and examined key proteins in the insulin signaling pathway using RNA sequencing (RNA-seq), KEGG pathway enrichment analysis, and Western blot (WB).

RESULTS

The CIH group showed a significant decrease in serum Ad levels, along with a corresponding increase in HOMA-IR, compared to the NC group. When Ad was administered to CIH mice, HOMA-IR decreased. Transcriptomic sequencing identified all the differentially expressed genes (DEGs) in eWAT among the three groups. KEGG pathway enrichment and WB analyses revealed the PI3K-AKT pathway as the key driver of functional changes in eWAT. The macrophage count and proportion in the eWAT of mice in the CIH group were significantly higher than in the NC and CIH + Ad groups, and the M1/M2 macrophage ratio was also notably increased. Levels of TNF-α, IL-6, and IL-1β in eWAT were considerably higher in the CIH group compared to both the NC and CIH + Ad groups.

CONCLUSION

CIH may impair insulin signaling pathways in mouse eWAT by promoting M1 polarization of eWAT macrophages, which is likely a key mechanism of CIH-induced insulin resistance. Additionally, it is hypothesized that Ad alleviates CIH-induced insulin resistance in mice by regulating eWAT macrophage polarization and restoring insulin signaling pathways.