PMID- 37130450 OWN - NLM STAT- MEDLINE DCOM- 20230623 LR - 20230623 IS - 1618-1298 (Electronic) IS - 0171-9335 (Linking) VI - 102 IP - 2 DP - 2023 Jun TI - GIPR expression is induced by thiazolidinediones in a PPARgamma-independent manner and repressed by obesogenic stimuli. PG - 151320 LID - S0171-9335(23)00035-3 [pii] LID - 10.1016/j.ejcb.2023.151320 [doi] AB - Adipose tissue (AT) dysfunctions are associated with the onset of insulin resistance (IR) and type 2 diabetes mellitus (T2DM). Targeting glucose-dependent insulinotropic peptide receptor (GIPR) is a valid option to increase the efficacy of glucagon-like peptide 1 (GLP-1) receptor agonists in T2DM treatment. Nevertheless, the therapeutic potential of targeting the GIP/GIPR axis and its effect on the AT are controversial. In this work, we explored the expression and regulation of GIPR in precursor cells and mature adipocytes, investigating if and how obesogenic stimuli and thiazolidinediones perturb GIPR expression. Using publicly available gene expression datasets, we assessed that, among white adipose tissue (WAT) cells, adipocytes express lower levels of GIPR compared to cells of mesothelial origin, pericytes, dendritic and NK/T cells. However, we report that GIPR levels markedly increase during the in vitro differentiation of both murine and human adipocytes, from 3T3-L1 and human mesenchymal precursor cells (MSCs), respectively. Notably, we demonstrated that thiazolidinediones - ie. synthetic PPARgamma agonists widely used as anti-diabetic drugs and contained in the adipogenic mix - markedly induce GIPR expression. Moreover, using multiple in vitro systems, we assessed that thiazolidinediones induce GIPR in a PPARgamma-independent manner. Our results support the hypothesis that PPARgamma synthetic agonists may be used to increase GIPR levels in AT, potentially affecting in turn the targeting of GIP system in patients with metabolic dysfunctions. Furthermore, we demonstrate in vitro and in vivo that proinflammatory stimuli, and especially the TNFalpha, represses GIPR both in human and murine adipocytes, even though discordant results were obtained between human and murine cellular systems for other cytokines. Finally, we demonstrated that GIPR is negatively affected also by the excessive lipid engulfment. Overall, we report that obesogenic stimuli - ie. pro-inflammatory cytokines and the increased lipid accumulation - and PPARgamma synthetic ligands oppositely modulate GIPR expression, possibly influencing the effectiveness of GIP agonists. CI - Copyright (c) 2023 The Authors. Published by Elsevier GmbH.. All rights reserved. FAU - Cataldi, Simona AU - Cataldi S AD - Institute of Genetics and Biophysics ''Adriano Buzzati-Traverso'', CNR, Via P. Castellino 111, 80131 Naples, Italy. FAU - Aprile, Marianna AU - Aprile M AD - Institute of Genetics and Biophysics ''Adriano Buzzati-Traverso'', CNR, Via P. Castellino 111, 80131 Naples, Italy. FAU - Perfetto, Caterina AU - Perfetto C AD - Institute of Genetics and Biophysics ''Adriano Buzzati-Traverso'', CNR, Via P. Castellino 111, 80131 Naples, Italy. FAU - Angot, Brice AU - Angot B AD - Universite Cote d'Azur, Inserm UMR1065, C3M, Team Cellular and Molecular Pathophysiology of Obesity, 06204 Nice, France. FAU - Cormont, Mireille AU - Cormont M AD - Universite Cote d'Azur, Inserm UMR1065, C3M, Team Cellular and Molecular Pathophysiology of Obesity, 06204 Nice, France. FAU - Ciccodicola, Alfredo AU - Ciccodicola A AD - Institute of Genetics and Biophysics ''Adriano Buzzati-Traverso'', CNR, Via P. Castellino 111, 80131 Naples, Italy; Department of Science and Technology, University of Naples ''Parthenope'', Naples, Italy. FAU - Tanti, Jean-Francois AU - Tanti JF AD - Universite Cote d'Azur, Inserm UMR1065, C3M, Team Cellular and Molecular Pathophysiology of Obesity, 06204 Nice, France. Electronic address: jean-francois.tanti@univ-cotedazur.fr. FAU - Costa, Valerio AU - Costa V AD - Institute of Genetics and Biophysics ''Adriano Buzzati-Traverso'', CNR, Via P. Castellino 111, 80131 Naples, Italy; NBFC, National Biodiversity Future Center, Palermo 90133, Italy. Electronic address: valerio.costa@igb.cnr.it. LA - eng PT - Journal Article DEP - 20230426 PL - Germany TA - Eur J Cell Biol JT - European journal of cell biology JID - 7906240 RN - 0 (PPAR gamma) RN - 0 (Thiazolidinediones) RN - 0 (Lipids) SB - IM MH - Humans MH - Mice MH - Animals MH - PPAR gamma/genetics/metabolism MH - *Diabetes Mellitus, Type 2/drug therapy/genetics/metabolism MH - *Thiazolidinediones/pharmacology/metabolism MH - Adipocytes/metabolism MH - Lipids/pharmacology OTO - NOTNLM OT - GIP receptor OT - Hypertrophic adipocytes OT - Inflammation OT - PPARgamma OT - Thiazolidinediones COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/05/02 18:41 MHDA- 2023/06/23 06:42 CRDT- 2023/05/02 18:00 PHST- 2022/09/30 00:00 [received] PHST- 2023/04/24 00:00 [revised] PHST- 2023/04/25 00:00 [accepted] PHST- 2023/06/23 06:42 [medline] PHST- 2023/05/02 18:41 [pubmed] PHST- 2023/05/02 18:00 [entrez] AID - S0171-9335(23)00035-3 [pii] AID - 10.1016/j.ejcb.2023.151320 [doi] PST - ppublish SO - Eur J Cell Biol. 2023 Jun;102(2):151320. doi: 10.1016/j.ejcb.2023.151320. Epub 2023 Apr 26.