The immune and metabolic systems interact closely with each other. Al-30WTRag2-/-(no T/B)Il2rg-/-Rag2-/-(no T/B/ILC)Rag2-/-Rorc-/-Rag2-/-(no ILC3)*** p< 0.0005**** p< 0.0001though various metabolic reactions are induced by malnutrition as well as overnutrition, little is known about the immune-metabolic crosstalk when nu-trient intake is inadequate. Thus, the long-term goal of our research is to under-stand the impact of the immune system on metabolism by taking advantage of a rodent fasting model. During fasting, fatty acids are converted in the liver into a metabolite called the ketone body. Ketone bodies are then utilized in the pe-ripheral tissues as an alternative energy source to glucose. This is important to maintain proper functions of tissues such as the brain, especially when glucose availability is limited. We observed that fasted Rag2-/- mice (lacking T cells and B cells), like wild-type (WT) mice, exhibited markedly elevated serum ketone body levels (Figure). On the other hand, serum ketone body levels in fasted Il-2rg-/-Rag2-/- mice (lacking T cells, B cells, and innate lymphoid cells (ILC)) were significantly lower compared with WT and Rag2-/- mice. These findings clearly indicate that immune cells, particularly ILCs, are involved in the regulation of ketogenesis. Based on differences in their functions and genetic profiles, ILCs are classified into three types, ILC1s, ILC2s, and ILC3s. Interestingly, serum ketone body levels during fasting were significantly lower in mice lacking ILC3s (Rorc-/-Rag2-/-) than in WT mice, suggesting that ILC3s play an important role in regulating ketogenesis. ILC3s are abundant in the small intestine and pro-duce robust levels of IL-17 and IL-22, which in turn regulate gut microbiota composition or turnover of intestinal epithelial cells. Then, how do ILC3s in the small intestine affect ketogenesis, which takes place in the liver? This is a key question that we want to answer and we are currently investigating its detailed mechanism.Figure: Ketogenesis and immune system(Left) Serum ketone body levels in WT, Rag2-/- and Il2rg-/-Rag2-/- mice.(Right) Serum ketone body levels in Rag2-/- and Rorc-/-Rag2-/- mice.Recent Major PublicationsOtaki N, Motomura Y, Terooatea T, Kelly ST, Mochizuki M, Takeno N, Koyasu S, Tamamitsu M, Sugihara F, Kikuta J, Kitamura H, Shiraishi Y, Miyanohara J, Nagano Y, Saita Y, Ogura T, Asano K, Minoda A, Moro K. Activation of ILC2s through constitutive IFNγ signaling reduction leads to spontaneous pulmonary fibrosis. Nat Commun 14, 8120 (2023)Takeuchi T, Kubota T, Nakanishi Y, Tsugawa H, Suda W, Kwon AT-J, Yazaki J, Ikeda K, Nemoto S, Mochizuki Y, Kitami T, Yugi K, Mizuno Y, Yamamichi N, Yamazaki T, Takemoto I, Kubota N, Kadowaki T, Arner E, Carninci P, Ohara O, Arita M, Hattori M, Koyasu S, Ohno H. Gut mi-crobial carbohydrate metabolism contributes to insulin resistance. Nature 621, 389-395 (2023)Laboratory for Immune Cell SystemsTeam Leader: Shigeo Koyasu
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