827 Psoriasis exacerbation by obesity reflects reduced adiponectin regulation of PPAR-γ/Th17 pathway activation and is reversal by adiponectin receptor agonism

Although obesity-related deficiency of adipokines is known to contribute increased psoriasis severity and decreased clinical response interventions, the mechanism by which it exacerbates poorly defined. We hypothesized that suppress activation innate immune responses in keratinocytes skin-resident Th17/γδ T cells. In preliminary studies, we confirmed diet-induced obese (DIO) mice had significantly lower serum adiponectin levels than lean when subjected topical imiquimod (IMQ) treatments induce psoriasis-like disease, supporting use this model for studies. We, then demonstrated DIO receiving daily injections mimetic peptide (ADP355) showed clinical, histological, transcriptional improvement only obese, not mice. ADP355 administration led a 2.1-fold increase cutaneous mRNA expression Adipoq (encoding adiponectin), suggesting directly agonizes receptor but also promotes endogenous expression. Flow cytometry revealed ADP355-administered reduced frequency cells lesional skin draining lymph nodes (51 % reduction; p<0.01), suppresses Il17a-secreting Our mechanistic studies using ChIP-assays human enhanced PPAR-γ binding regulatory regions psoriatic genes (5.4-, 3.4-, 2.7-fold increase, respectively, IL23, IL17RA, LOR binding; all p<0.005) inhibit IL23 (63 p=0.0164), PI3 p=0.0002), IL17RA (46 p=0.0151) stimulate (2-fold p=0.014). findings suggest limits activating pathway thereby suppressing Th17 activation. Small molecule therapy may be an effective adjunctive individuals.