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

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

doi:10.3389/fimmu.2021.643144

Abstract

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 (Gipr-/- BM) and GIPR/S100A8/A9 (Gipr-/-/S100a9-/- 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 Giprfl/fl mice and Lyz2cre/+ mice (LysMΔGipr). Under both short and progressive HFD regimens, Gipr-/- 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+ regulatory T cells (Tregs). Co-deletion of S100A8/A9 in Gipr-/- immune cells reversed the impairment of type 2 cytokine expression in epiWAT, suggesting a mechanistic role for this alarmin in type 2 immune suppression. LysMΔGipr 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.

Highlights

Integrated immunometabolic responses couple dietary intake, energy utilization, and storage to immune regulation of tissue function, and are essential for the maintenance and restoration of homeostasis [1]
Given the impairment in the production of type 2 immune mediators in the epididymal visceral WAT (epiWAT) during high-fat diet (HFD) induced by GIPRdeficiency in immune cells (Figure 1), we examined the representation of key associated type 2 immune cells in the epiWAT stromal vascular fracture (SVF) of wild type (WT) bone marrow (BM) vs. Gipr-/
Given the increased expression of the beiging-interfering cytokine IL10 in the epiWAT of Gipr-/- BM (Figure 1F) and LysMDGipr mice (Figure 4C) under prolonged HFD, we examined the effect of the GlucoseDependent Insulinotropic Polypeptide (GIP) analogue on cytokine expression in response to coldchallenge

Summary

Introduction

Integrated immunometabolic responses couple dietary intake, energy utilization, and storage to immune regulation of tissue function, and are essential for the maintenance and restoration of homeostasis [1]. Glucagon-like Peptide-1 (GLP-1) and GlucoseDependent Insulinotropic Polypeptide (GIP), secreted by gut L and K cells, respectively, have attracted great interest in view of their metabolic roles and therapeutic potential [3, 4] Both hormones are known for their glucose-dependent insulinotropic actions on the pancreas via G-protein coupled receptors expressed on pancreatic islet cells (the incretin effect) [3]. The directional importance of GIP in obesity-associated inflammatory responses is surrounded by controversy, with studies reporting both pro[8, 9] and anti-inflammatory [10, 11] effects in the white adipose tissue (WAT) These opposing results likely reflect the integrated pleiotropic functions of GIP in different tissues and cells, and the utilization in many studies of GIP analogues that can serve as both agonists and antagonists [12]. In contrast to the overall metabolic protection of mice with stimuli global germline inactivation of the GIPR [14], bone marrow (BM) chimeric mice with immune cell-targeted GIPR-deficiency (Gipr-/- BM) display greater weight gain during HFD feeding, despite similar food intake, concomitantly with increased insulin resistance and hepatic steatosis [13]

Methods

Results

Conclusion