Abstract Text: Inflammatory bowel disease (IBD), comprising of Crohn’s Disease and Ulcerative Colitis, is a debilitating disease with no known cause. Although extensive work has linked numerous genetic loci to IBD, most of these associations remain poorly understood. Some studies have suggested that IBD and metabolic diseases are associated. Whether these two diseases are indeed linked and what the molecular and pathophysiological mechanisms behind this association is unknown. Here, we show that DUPD1, a phosphatase of unknown function mechanistically links both IBD and metabolic disease. Specifically, Dupd1-/- mice were protected from high fat diet (HFD)-induced obesity, fatty liver, and glucose intolerance. Dupd1-/- mice were also protected from dextran sodium sulfate (DSS) and Helicobacter hepaticus induced colitis, as well as DSS/Azoxymethane (AOM) induced colitis-associated colon cancer (CAC). The expression of DUPD1 is largely restricted to the skeletal muscle. Indeed, using skeletal muscle specific conditional DUPD1 knockout mice (Dupd1fl/fl Myf6Cre), we show that DUPD1 exerts its colitogenic effects from the skeletal muscle by promoting systemic inflammation and through the modulation of autophagy within the skeletal muscle. Our study suggests that IBD has a metabolic component and that the skeletal muscle acts as an immunological organ capable of regulating inflammation at distant sites. This study further implicates DUPD1 as a potential novel therapeutic target in IBD and obesity-associated metabolic diseases.
