The helminth glycoprotein omega-1 improves metabolic homeostasis in obese mice through type-2 immunity-independent inhibition of food intake
Authors: van der Zande Hendrik J.P. , Gonzalez Michael A. , de Ruiter Karin , Wilbers Ruud , Garcia-Tardón Noemi , van Huizen Mariska , van Noort Kim , Pelgrom Leonard R. , Lambooij Joost M. , Zawistowska-Deniziak Anna , Otto Frank , Ozir-Fazalalikhan Arifa , van Willigen Danny , Welling Mick , Poles Jordan , van Leeuwen Fijs , Hokke Cornelis H. , Schots Arjen , Yazdanbakhsh Maria , Loke P’ng , Guigas Bruno 
Published: July 2020

AbstractType 2 immunity plays an essential role in the maintenance of metabolic homeostasis and its disruption during obesity promotes meta-inflammation and insulin resistance. Infection with the helminth parasiteSchistosoma mansoniand treatment with its soluble egg antigens (SEA) can induce a type 2 immune response in metabolic organs and improve insulin sensitivity and glucose tolerance in obese mice, yet a causal relationship remains unproven. Here, we investigated the effects and underlying mechanisms of the T2 ribonuclease omega-1 (ω1), one of the majorS. mansoniimmunomodulatory glycoproteins, on metabolic homeostasis. Male C57Bl6/J mice were fed a high-fat diet for 12 weeks followed by bi-weekly injection of SEA, ω1 or vehicle for 4 additional weeks. Whole-body metabolic homeostasis and energy expenditure were assessed by glucose/insulin tolerance tests and indirect calorimetry, respectively. Tissue-specific immune cell phenotypes were determined by flow cytometry. We show that treatment of obese mice with plant-produced recombinant ω1, harboring similar glycan motifs as present on the native molecule, decreased body fat mass and improved systemic insulin sensitivity and glucose tolerance in a time-and dose-dependent manner. This effect was associated with an increase in white adipose tissue (WAT) type 2 T helper cells, eosinophils and alternatively-activated macrophages, without affecting type 2 innate lymphoid cells. In contrast to SEA, the metabolic effects of ω1 were still observed in obese STAT6-deficient mice with impaired type 2 immunity, indicating that its metabolic effects are independent of the type 2 immune response. Instead, we found that ω1 inhibited food intake, without affecting locomotor activity, WAT thermogenic capacity or whole-body energy expenditure, an effect also occurring in leptin receptor-deficient obese and hyperphagicdb/dbmice. Altogether, we demonstrate that while the helminth glycoprotein ω1 can induce type 2 immunity, it improves whole-body metabolic homeostasis in obese mice by inhibiting food intake via a STAT6-independent mechanism.Author summaryThe obesity-induced chronic low-grade inflammation, notably in adipose tissue, contributes to insulin resistance and increased risk of type 2 diabetes. We have previously shown that infection with parasitic helminth worms was associated with protection against obesity-related metabolic dysfunctions both in mice and humans. We have also reported that treatment of obese mice with an extract ofSchistosoma mansonieggs (SEA) improves insulin sensitivity and glucose tolerance, a beneficial effect that was associated with a helminth-specific type 2 immune response in metabolic organs. Here, we studied the effects of omega-1 (ω1), a single immunomodulatory molecule from SEA, on metabolic health in obese mice, and investigated the role of the host immune response elicited. We found that ω1 induced a helminth-characteristic type 2 immune response in adipose tissue and improved both insulin sensitivity and glucose tolerance in obese mice. Yet, in contrast to SEA, ω1’s immunomodulatory properties were dispensable for its metabolic effects. Instead, we show that ω1 inhibited food intake, a feature accounting for most of the improvements in metabolic health. Together, our findings indicate that helminth molecules may improve metabolic health through multiple distinct mechanisms, and further characterization of such molecules could lead to new therapeutic strategies to combat obesity.