Obesity control by SHIP inhibition requires pan-paralog inhibition and an intact eosinophil compartment
Sandra Fernandes,
Neetu Srivastava,
Chiara Pedicone,
Raki Sudan,
Elizabeth A. Luke,
Otto M. Dungan,
Angela Pacherille,
Shea T. Meyer,
Shawn Dormann,
Stéphane Schurmans,
Benedict J. Chambers,
John D. Chisholm,
William G. Kerr
Affiliations
Sandra Fernandes
Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA
Neetu Srivastava
Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA
Chiara Pedicone
Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA
Raki Sudan
Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA
Elizabeth A. Luke
Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA
Otto M. Dungan
Department of Chemistry, Syracuse University, Syracuse, NY, USA
Angela Pacherille
Department of Chemistry, Syracuse University, Syracuse, NY, USA
Shea T. Meyer
Department of Chemistry, Syracuse University, Syracuse, NY, USA
Shawn Dormann
Department of Chemistry, Syracuse University, Syracuse, NY, USA
Stéphane Schurmans
GIGA Research Centre, Université de Liège, Liège, Belgium
Benedict J. Chambers
Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden
John D. Chisholm
Department of Chemistry, Syracuse University, Syracuse, NY, USA
William G. Kerr
Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA; Department of Chemistry, Syracuse University, Syracuse, NY, USA; Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY, USA; Corresponding author
Summary: 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.
