These studies identify a functional gut hormone-BM axis positioned for transduction of signals linking nutrient availability to the control of TLR and Notch genes regulating hematopoiesis.
However, the magnitude of the cellular changes in hematopoiesis in response to gain or loss of GIPR signaling was relatively modest. GIPR agonism modified BM gene expression profiles following 5-FU and PAM3CSK4 whereas loss of the Gipr altered the hematopoietic responses to energy excess, two TLR ligands and 5-FU. Loss of the BM GIPR attenuates the extent of adipose tissue inflammation, and dysregulates the hematopoietic response to BMT. Nevertheless, gain and loss of function studies revealed that GIPR signaling controls expression of BM Toll-like receptor (TLR) and Notch-related genes regulating hematopoiesis. Gipr is expressed within T cells, myeloid cells and myeloid precursors, however these cell populations were not different in peripheral blood, spleen or BM of Gipr-/- and GiprTie2-/- mice.
Bone marrow responses were studied in (i) mice fed regular or energy-rich diets, (ii) mice treated with hematopoietic stressors including acute 5-fluorouracil (5-FU), Lipopolysaccharide (LPS), and Pam3CysSerLys4 (Pam3CSK4)), with or without pharmacological administration of a GIPR agonist and (iii) mice with global (Gipr-/-) or selective deletion of the GIPR (GiprTie2-/-) with and without bone marrow transplantation (BMT). We assessed the expression of the Gipr in BM lineages and examined functional roles for the GIPR in control of hematopoiesis. However the importance of gain and loss of GIPR signaling for diverse hematopoietic responses remains unclear. The GIP Receptor (GIPR) is also expressed in the bone marrow, notably in cells of the myeloid lineage. Glucose-dependent insulinotropic polypeptide (GIP) conveys information from ingested nutrients to peripheral tissues, signaling energy availability.
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