Sfrp5 and Wnt5a: novel regulators of cytokine release and insulin action through the non-canonical Wnt-signalling pathway in primary human adipocytes and hepatocytes?

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Secreted frizzled-related protein (Sfrp)5 is an inhibitor of the wingless-type MMTV integration site family member Wnt5a which activates the non-canonical Wnt-signalling pathway. Several mainly preclinical studies recently reported a role of Sfrp5 and Wnt5a in the pathogenesis of type 2 diabetes (T2D), but it has become increasingly clear that data from mouse models cannot be translated to humans. Mouse studies described Sfrp5 as anti-inflammatory and insulin-sensitising, whereas Wnt5a showed opposite effects. Preliminary results from human studies indicate a more complex interaction of these factors with inflammation and glucose metabolism. Thus, the proposed project aims to clarify how this protein duo influences these diabetes-associated processes and the risk of incident of T2D in humans. I hypothesise that obesity alters the secretion pattern of Sfrp5 and Wnt5a from different cell types into the circulation. From there both proteins reach insulin target tissues and affect cytokine release, insulin-sensitive glucose and energy metabolism. I expect that the underlying mechanism is based on the non-canonical Wnt-signalling pathway because 5 Wnt-signalling members are known to regulate cytokine release and/or insulin resistance: JNK, PKC, NFAT, NFkappaB and CREB. I further assume that the ratio of Sfrp5 and Wnt5a determines the degree of the activation status of the non-canonical Wnt-signalling pathway and therefore the risk of T2D. I plan to approach this hypothesis on three different levels which allow a translational analysis of the role of Sfrp5 and Wnt5a in the pathogenesis of T2D: My first analysis is based on a clinical level to determine how obesity and weight loss regulate Sfrp5 and Wnt5a (objective 1). I will measure the concentrations of Sfrp5 and Wnt5a in serum and insulin target tissues such as liver, skeletal muscle and adipose tissues obtained from lean controls and obese participants of the Bariatrix study before and after abdominal surgery. My second analysis is based on a cellular level in vitro to study how and by which component(s) of the non-canonical Wnt-signalling pathways an imbalance of Sfrp5 and Wnt5a affects secretion pattern and insulin-sensitive glucose and energy metabolism (objective 2&3). For this part, I will use primary human adipocytes and hepatocytes. My third analysis is based on an epidemiological level to evaluate to what extent systemic levels of Sfrp5 and Wnt5a serve as predictors of incident T2D in a prospective population-based study (objective 4). I will measure concentrations of Sfrp5 and Wnt5a in serum samples from 1000 well-phenotyped participants of the KORA study and relate them to the T2D status at the 7-year follow-up. The proposed project aims to shed light on the hitherto unknown link between Sfrp5/Wnt5a, non-canonical Wnt-signalling pathway and T2D. A deeper insight into these interactions might reveal novel therapeutic targets in the prevention and treatment of T2D.