Sex-specific effects of adiponectin on AdipoR1/R2 in macrophages from individuals with cardiovascular risk factors.

Abstract

Background and aims: Monocyte-derived macrophages (MDMs) are key innate immune cells involved in all stages of atherosclerosis. Adiponectin is an anti-inflammatory hormone that modulates macrophage functions by interacting with adiponectin receptor (AdipoR)1 and AdipoR2. However, sex-specific AdipoR patterns in macrophages among people at risk for atherosclerosis have not been investigated. We evaluated the effects of adiponectin in MDMs on AdipoR1/R2 gene expression and inflammatory responses between males and females with cardiovascular (CV) risk factors and without atherosclerosis.

Methods and results: Our proof-of-concept cross-sectional study included males and females who had two or more CV risk factors without overt atherosclerosis. Blood samples were collected to isolate serum and CD14⁺ monocytes, which were differentiated into macrophages and cultured with adiponectin. MDMs and media were collected to assess AdipoR1/R2 gene expression and inflammatory profiles, respectively. Adiponectin-cultured MDMs from males (n = 6) did not alter AdipoR1 mRNA levels, but decreased AdipoR2 and peroxisome proliferator-activated receptor (PPAR)-α mRNA; in females (n = 7), AdipoR1 mRNA was increased, while AdipoR2 and PPAR-α remained unchanged compared to control MDMs. In both males and females, adiponectin induced the release of TNF-α, IL-6 and IL-10 from MDMs, in addition to MCP-1, IFN-γ, IL-1β, and IL-12p40 in males.

Conclusions: Adiponectin-cultured MDMs from males reduced AdipoR2-PPAR-α signaling and produced a heterogenous inflammatory profile. In contrast, adiponectin-cultured MDMs from females increased AdipoR1 gene expression and did not alter AdipoR2-PPAR-α signaling. This suggests that early interventions via an AdipoR2-targeted approach may benefit the CV health of males at risk for atherosclerosis.