AUTHOR=Efimova Irina , Steinberg Inbar , Zvibel Isabel , Neumann Anat , Mantelmacher Dana Fernanda , Drucker Daniel J. , Fishman Sigal , Varol Chen 

TITLE=GIPR Signaling in Immune Cells Maintains Metabolically Beneficial Type 2 Immune Responses in the White Fat From Obese Mice

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.643144

DOI=10.3389/fimmu.2021.643144

ISSN=1664-3224

ABSTRACT=<p>Glucose-dependent insulinotropic polypeptide (GIP) communicates information on energy availability from the gut to peripheral tissues. Disruption of its signaling in myeloid immune cells during high-fat diet (HFD)-induced obesity impairs energy homeostasis due to the unrestrained metabolically deleterious actions of S100A8/A9 alarmin. White adipose tissue (WAT) type 2 immune cell networks are important for maintaining metabolic and energy homeostasis and limiting obesity-induced inflammation. Nevertheless, the consequences of losing immune cell GIP receptor (GIPR) signaling on type 2 immunity in WAT remains unknown. Bone marrow (BM) chimerism was used to generate mice with GIPR (<italic>Gipr<sup>-/-</sup></italic> BM) and GIPR<italic>/</italic>S100A8/A9 <italic>(Gipr<sup>-/-</sup></italic>/<italic>S100a9<sup>-/-</sup></italic> BM) deletion in immune cells. These mice were subjected to short (5 weeks) and progressive (14 weeks) HFD regimens. GIPR-deficiency was also targeted to myeloid cells by crossing <italic>Gipr<sup>fl/fl</sup></italic> mice and <italic>Lyz2<sup>cre/+</sup></italic> mice (<italic>LysM<sup>ΔGipr</sup></italic>). Under both short and progressive HFD regimens, <italic>Gipr<sup>-/-</sup></italic> BM mice exhibited altered expression of key type 2 immune cytokines in the epididymal visceral WAT (epiWAT), but not in subcutaneous inguinal WAT. This was further linked to declined representation of type 2 immune cells in epiWAT, such as group 2 innate lymphoid cells (ILC2), eosinophils, and FOXP3<sup>+</sup> regulatory T cells (Tregs). Co-deletion of S100A8/A9 in <italic>Gipr<sup>-/-</sup></italic> immune cells reversed the impairment of type 2 cytokine expression in epiWAT, suggesting a mechanistic role for this alarmin in type 2 immune suppression. <italic>LysM<sup>ΔGipr</sup></italic> mice on HFD also displayed altered expression of type 2 immune mediators, highlighting that GIPR-deficiency in myeloid immune cells is responsible for the impairment of type 2 immune networks. Finally, abrogated GIPR signaling in immune cells also affected adipocyte fraction cells, inducing their increased production of the beiging interfering cytokine IL-10 and stress- related type 2 cytokine IL-13. Collectively, these findings attribute an important role for GIPR in myeloid immune cells in supporting WAT type 2 immunity.</p>