Eva1 deficiency prevents obesity-induced metabolic disorders by reducing visceral adipose dysfunction

Epithelial V-like antigen 1 (Eva1) is a highly specific marker for brown adipose tissue (BAT) in both mice and humans, but its metabolic function remains unclear. We investigated the impact of Eva1 deletion on the development of obesity.

To assess the metabolic role of Eva1, we generated whole-body and adipocyte-specific Eva1^{knockout (KO)} mice, which were subjected to a high-fat diet (HFD) for 12 weeks and characterized metabolic phenotypes. To further elucidate the depot-dependent impact of Eva1 deficiency, we performed histological analysis and 3' mRNA-seq of BAT and epididymal visceral white adipose tissue (eWAT). To investigate the role of macrophage-derived Eva1 in obesity development, we transplanted wild-type (WT) or Eva1^KO macrophages into Eva1^KO mice fed an HFD.

We found that whole-body Eva1^KO mice are resistant to HFD-induced obesity, insulin resistance and visceral adipose inflammation. However, Eva1 deletion in adipocytes, both brown and white, did not phenocopy these protective effects. Notably, whole-body Eva1 deficiency triggers functional changes in eWAT, but not in BAT. These results led us to investigate a possible involvement of macrophages in Eva1-mediated obesity regulation. We found that Eva1 is expressed in macrophages and plays a role in lipopolysaccharide (LPS)-induced inflammatory responses, possibly through the direct interaction with toll-like receptor 4 (TLR4). Moreover, Eva1^KO mice exhibited improved survival rates in the face of severe sepsis induced by LPS. Importantly, transplantation of WT macrophages to Eva1^KO mice abolished the beneficial effects of whole-body Eva1 deletion against obesity and visceral adipose inflammation.

Our findings highlight macrophage-derived Eva1 as an important mediator in obesity-induced eWAT remodeling, suggesting that targeting Eva1 could offer a novel therapeutic strategy for obesity-related metabolic disorders.