The inflammatory skin disease psoriasis is an independent risk-factor for development of insulin resistance. However, the underlying mechanisms remain poorly elucidated. We used human and mouse models of psoriasis to investigate a potential endocrine role of the skin in regulating subcutaneous adipose tissue (sAT) and pancreatic islet function. Mice were administered a daily topical dose (75 mg) of imiquimod (IMQ), or Vaseline control, to a shaved dorsal region for 4 days. IPGTT were conducted to assess glucose tolerance and insulin secretion in vivo; skin, sAT and whole pancreas were collected on day 5 for further analysis. Human explant skin was treated with IMQ to induce a psoriasis-like phenotype and cultured for 24h. Conditioned media (CM) was collected, diluted 1:1 with fresh media and used to treat human explant sAT or mouse islets (24h). These experiments were also conducted using CM obtained from culturing IMQ-mouse skin. IMQ induced an inflammatory phenotype in human and mouse skin compared to controls. IMQ-mice displayed increased inflammation and decreased GLUT4 in sAT, indicative of sAT insulin resistance, whilst fed serum insulin levels were elevated (1.44±0.23 ng/ml vs 0.47±0.15 ng/ml, n=1214; P<0.01). However, IMQ-mice displayed improved glucose tolerance and increased glucose-stimulated insulin secretion (GSIS) and c-peptide secretion together with increased Ki67+ beta-cells (1.46±0.19 vs 0.52±0.10, n=34; P<0.001). In support of a direct endocrine role of the skin, incubation of human or mouse sAT with IMQ-skin CM (obtained from human or mouse skin) also led to increased inflammation and reduced GLUT4 expression in sAT. Incubation of mouse islets with human IMQ-skin CM increased GSIS, indicative of islet compensation to insulin resistance. These findings show that skin inflammation induces sAT insulin resistance and increased pancreatic islet function, in vivo and ex vivo, likely via the effects of skin-derived factors.