Systemic inflammation-induced adipose tissue remodeling drives psoriasis exacerbation in obesity through epigenetic and immunometabolic dysregulation.

Disruption of adipose tissue homeostasis is increasingly recognized as a key driver of psoriatic inflammation in the context of obesity. However, the mechanisms linking adipose dysfunction to disease severity remain incompletely understood. We employed an obese mouse model of psoriasis induced by topical imiquimod application or dermal IL-23 injection. Inflammatory profiling from these mice was integrated with multi-omic single-nucleus sequencing targeting RNA and chromatin accessibility to investigate genetic and epigenetic alterations in adipose tissue. Obese mice developed markedly aggravated psoriatic dermatitis following imiquimod treatment, accompanied by increased systemic inflammatory responses and a significant reduction in fat mass. Histological and molecular analyses revealed extensive monocyte-macrophage infiltration into perigonadal adipose tissue, increased expression of pro-inflammatory genes, and upregulation of cell death-associated molecules in obese mice relative to lean counterparts. In contrast, IL-23 injection elicited comparable skin inflammation in both lean and obese mice without inducing adipose tissue loss or systemic inflammation. Multi-omic profiling of imiquimod-treated obese mice revealed genetic and epigenetic changes in adipocytes that promote fatty acid consumption. Furthermore, a shift was observed in macrophage populations-from a lipid-associated subset with active intercellular communication in IL-23-treated mice to disorganized macrophage compartments with monocyte accumulation in imiquimod-treated mice. These findings suggest that obesity sensitizes adipose tissue to homeostatic disruption, establishing it as a critical immunometabolic interface that drives psoriasis exacerbation in response to systemic inflammatory cues.