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

Rationale: 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. Methods: 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. Results: 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. Conclusions: 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.