@article{f4918585b005442a80136e7278f800cd,
title = "Obesity control by SHIP inhibition requires pan-paralog inhibition and an intact eosinophil compartment",
abstract = "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.",
keywords = "Human metabolism, Immunology, Molecular biology",
author = "Sandra Fernandes and Neetu Srivastava and Chiara Pedicone and Raki Sudan and Luke, {Elizabeth A.} and Dungan, {Otto M.} and Angela Pacherille and Meyer, {Shea T.} and Shawn Dormann and St{\'e}phane Schurmans and Chambers, {Benedict J.} and Chisholm, {John D.} and Kerr, {William G.}",
note = "Funding Information: WGK is the Alfred T. Murphy Family Professor of Pediatric Hematology/Oncology and an Empire Scholar of the State University of NY. Additionally, W.G.K. and J.D.C. receive support from NIH grant RO1 AG059717. S.F. N.S. and W.G.K designed, analyzed, wrote and edited the manuscript. S.F. N.S. C.P. R.S. and E.L. performed obesity related experiments, analyzed data and generated figures. S.S. provided SHIP2flox mice, intellectual input and comments on the text. B.J.C. provided crucial intellectual input concerning the identificaiton of ILC2 cells by cytometry and modulation of ST2 surface expression. O.M.D. A.P. S.T.M. and J.D.C. synthesized 3AC, K118, K161 and K149 used in these studies. W.G.K, S.F. C.P. and J.D.C have patents, pending and issued, concerning the analysis and targeting of SHIP1 and SHIP2 in disease. The other authors have no interests to declare. Funding Information: WGK is the Alfred T. Murphy Family Professor of Pediatric Hematology/Oncology and an Empire Scholar of the State University of NY. Additionally, W.G.K. and J.D.C. receive support from NIH grant RO1 AG059717 . Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = feb,
day = "17",
doi = "10.1016/j.isci.2023.106071",
language = "English (US)",
volume = "26",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier",
number = "2",
}