Obesity control by SHIP inhibition requires pan-paralog inhibition and an intact eosinophil compartment

Fernandes, S.; Srivastava, N.; Pedicone, C.; Sudan, R.; Luke, E. A.; Dungan, O. M.; Pacherille, A.; Meyer, S. T.; Dormann, S.; Schurmans, Stéphane; Jacobsen, E.; Chisholm, J. D.; Kerr, W. G.

doi:10.1016/j.isci.2023.106071

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Obesity control by SHIP inhibition requires pan-paralog inhibition and an intact eosinophil compartment

Fernandes, S.; Srivastava, N.; Pedicone, C. et al.

2023 • In iScience

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https://hdl.handle.net/2268/299930

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10.1016/j.isci.2023.106071

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Keywords :

obesity, phosphoinositide, 5-phosphatase, Ship1, Ship2, Inppl1, eosinophil; Inpp5D

Abstract :

[en] Here we extend the understanding of how chemical inhibition of SHIP paralogs controls obesity. We compare different classes of SHIP inhibitors and find that selective inhibitors of SHIP1 or SHIP2 are unable to prevent weight gain and body fat accumulation during increased caloric intake. Surprisingly, only pan-SHIP1/2 inhibitors (pan-SHIPi) prevent diet-induced obesity. We confirm that pan-SHIPi is essential by showing that dual treatment with SHIP1 and SHIP2 selective inhibitors reduced adiposity during excess caloric intake. Consistent with this, genetic inactivation of both SHIP paralogs in eosinophils or myeloid cells also reduces obesity and adiposity. In fact, pan-SHIPi requires an eosinophil compartment to prevent diet-induced adiposity, demonstrating that pan-SHIPi acts via an immune mechanism. We also find that pan-SHIPi increases ILC2 cell function in aged, obese mice to reduce their obesity. Finally, we show that pan-SHIPi also reduces hyperglycemia, but not via eosinophils, indicating a separate mechanism for glucose control.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Fernandes, S.

Srivastava, N.

Pedicone, C.

Sudan, R.

Luke, E. A.

Dungan, O. M.

Pacherille, A.

Meyer, S. T.

Dormann, S.

Schurmans, Stéphane ; Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Functional Genetics

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Language :

English

Title :

Obesity control by SHIP inhibition requires pan-paralog inhibition and an intact eosinophil compartment

Publication date :

2023

Journal title :

iScience

eISSN :

2589-0042

Publisher :

Elsevier, Cambridge, United States - Massachusetts

Peer reviewed :

Peer Reviewed verified by ORBi

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since 11 February 2023

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