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    • To directly address whether pharmacological

    2021-09-17

    To directly address whether pharmacological attenuation of physiological GIP provides therapeutic benefits in obese mice, we pursued a selective long-acting antagonist to complement the work we report on GIPR agonism. We report a GIP analog of sufficient aqueous solubility that employs a shortened N-terminus [30], the Arg18 substitution, and a site-specific fatty-acylation to achieve selective, high potency antagonism at mouse and human GIPR. While this acyl GIPR antagonist is of lesser potency at mGIPR relative to hGIPR and could benefit from further chemical refinement if it were to be advanced to clinical study, it is suitable for preclinical pharmacology study in mice. This acylated GIPR antagonist blocked GIPR agonist-induced improvements in glucose tolerance in DIO mice, and had no apparent effect on body weight in DIO mice following high dose chronic therapy, demonstrating that inhibition of endogenous GIP does not promote body weight loss. Co-treatment of liraglutide with this acyl GIPR antagonist also did not result in additional body weight lowering benefit, which importantly was evident upon co-treatment with GIPR agonists. These collective results once again illustrate the amplification of GLP-1R agonist-induced weight lowering with GIPR agonism [5], [8], and not with GIPR antagonism. The pharmacokinetic profile of this antagonist was not studied but is expected to be comparable to the acylated agonist that we utilized. These results of synergistic body weight lowering with co-agonism and no evidence of anti-obesity activity in GIPR antagonism when administered alone or in concert with GLP-1 agonism convincingly addresses the primary objective of this report. The mechanism of action that drives the body weight lowering benefits of GIPR agonism has yet to be fully elucidated, and is not the primary purpose of this report. The body weight loss induced by selective mGIPR agonism appears to be predominantly driven by food intake, as interpreted from pair-feeding and indirect calorimetry studies, which is consistent with previous studies of co-agonists [5], [8]. Although not studied here, this suggests the engagement of neural circuits in the AVL-301 involved in feeding regulation, which is consistent with central food intake suppression observed after central administration of GIP and GLP-1 [44]. Whether the engagement is directly mediated by GIPR signaling in the brain is a question that remains to be investigated, but the lack of weight-lowering effects of other GIPR agonists in leptin-deficient mice [25] suggests a peripheral to central connection. As GIPR is expressed in adipose tissues and involved in various aspects of lipid homeostasis [45], GIPR-mediated body weight lowering could be the consequence of improved insulin sensitivity, thus lessening the dysregulated lipogenesis observed in hyperinsulinemic obesity, which could explain the lack of body weight lowering observed in insulinopenic obese mice when other GIP analogs were used [25]. GIPR mediated effects on immunometabolism can also contribute to improved systemic metabolism and adipocyte function [46]. It also cannot be excluded that the preferential direction to manipulate the GIPR system can differ based on tissue and site of action such that analogs that favor more central nervous system biodistribution or analogs that have tissue-specific receptor modulator function, such as selective antagonism at adipose GIPR and functional agonism at islet, myeloid, and brain GIPR, would be beneficial. We expect that the use of quality pharmacological tools as reported here, in combination with precise GIPR expression mapping, conditional Gipr−/− mice, and more sophisticated pharmacology studies will be valuable in delineating the mechanisms driving the therapeutic benefits of GIP action on body weight control.
    Conclusion
    Author contributions P.A.M. conceptualized the project, synthesized agonists, performed in vitro assays, and interpreted data. B.F. conceptualized the project, performed in vivo pharmacology experiments, interpreted data, and co-wrote the manuscript. V.G. performed in vitro assays and interpreted data. B.Y. synthesized antagonists and interpreted data. M.H.T interpreted data and edited the manuscript. R.D.D. conceptualized the project, interpreted data, co-wrote the manuscript, and is the guarantor of the work. D.P.-T. conceptualized the project, interpreted data, and co-wrote the manuscript.