BNIP3-mediated mitophagy in macrophages regulates obesity-induced adipose tissue metaflammation
Sangseob Kim, Cheoljun Choi, Yeonho Son, Junhyuck Lee, Sungug Joo, Yun‐Hee Lee
Abstract
Adipose tissue macrophages (ATMs) are key cellular components that respond to nutritional excess, contributing to obesity-induced inflammation and insulin resistance. However, the mechanisms underlying macrophage polarization and recruitment in adipose tissue during obesity remain unclear. In this study, we investigated mitophagy-dependent metabolic reprogramming in ATMs and identified a crucial role of the mitophagy receptor BNIP3 in regulating macrophage polarization in response to obesity. Mitophagic flux in ATMs increased following 12 weeks of high-fat diet (HFD) feeding, with Bnip3 levels upregulated in a HIF1A dependent manner, without affecting other mitophagy receptors. Macrophage-specific bnip3 knockout reduced HFD-induced adipose tissue inflammation and improved glucose tolerance and insulin sensitivity. Mechanistically, hypoxic conditions in vitro induced HIF1A-BNIP3-mediated mitophagy and glycolytic shift in macrophages. Furthermore, HIF1A-BNIP3 signaling-enhanced lipopolysaccharide-induced pro-inflammatory activation in macrophages. These findings demonstrate that BNIP3-mediated mitophagy regulates the glycolytic shift and pro-inflammatory polarization in macrophages and suggest that BNIP3 could be a therapeutical target for obesity-related metabolic diseases.