A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity

In obesity, white adipose tissue (AT) inflammation is associated with reduced beige adipogenesis, a thermogenic and energy-dissipating function mediated by uncoupling protein-1 (UCP1)-expressing beige adipocytes. Here, we dissected an inflammation-driven inhibitory mechanism of beige adipogenesis in obesity that required direct adhesive interactions between macrophages and adipocytes mediated, respectively, by α(4) integrin and its counter-receptor VCAM-1, the expression of which was upregulated in obesity. This adhesive interaction reciprocally and concomitantly modulated inflammatory activation in macrophages and Erk-dependent downregulation of UCP1 in adipocytes. Genetic or pharmacologic inactivation of α(4) integrin in mice resulted in elevated UCP1 expression and beige adipogenesis of the subcutaneous AT in obesity. Our findings, established in both mouse and human systems, reveal a self-sustained cycle of inflammation-driven impairment of beige adipogenesis in obesity.