The helminth glycoprotein omega‐1 improves metabolic homeostasis in obese mice through type 2 immunity‐independent inhibition of food intake

Hendrik J.P. van der Zande, Michael A. Gonzalez, Karin Ruiter, Ruud H.P. Wilbers, Noemí García‐Tardón, Mariska van Huizen, Kim van Noort, Leonard R. Pelgrom, Joost M. Lambooij, Anna Zawistowska‐Deniziak, Frank Otto, Arifa Ozir‐Fazalalikhan, Danny van Willigen, Mick Welling, Jordan Poles, Fijs Leeuwen, Cornelis H. Hokke, Arjen Schots, Maria Yazdanbakhsh, P. LokeBruno Guigas*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Type 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 parasite Schistosoma mansoni and treatment with its soluble egg antigens (SEA) 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 major S mansoni immunomodulatory glycoproteins, on metabolic homeostasis. 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 hyperphagic db/db mice. 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.
Original languageEnglish
Article numbere21331
JournalFASEB Journal
Volume35
Issue number2
DOIs
Publication statusPublished - Feb 2021

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