Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism

Killion, Elizabeth A.; Chen, Michelle; Falsey, James R.; Sivits, Glenn; Hager, Todd; Atangan, Larissa; Helmering, Joan; Lee, Jae; Li, Hongyan; Wu, Bin; Cheng, Yuan; Véniant, Murielle M.; Lloyd, D. J.

doi:10.1038/s41467-020-18751-8

Cited by 84 publications

(75 citation statements)

References 36 publications

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“…While loss-of-function studies indicate that GIP drives weight gain, when it comes to GIPR agonism and antagonism, compelling evidence paradoxically indicate that both approaches can reduce body weight, especially if combined with GLP-1 agonists (12,59). This paradox may reflect the partial agonistic activity of certain antagonists (60), compensatory relationship and overlapping signaling axes between GIPR and GLP-1R incretin receptors (59,61), as well as desensitization of GIPR achieved by chronic agonism (62). With respect to the latter, in cultured mouse or human preadipocytes, exposure to 1 mM dAla2-GIP for 24 h decreased cAMP response to subsequent GIPR stimulation up to 48 h (62), indicating that chronic GIPR agonism functionally mimics GIPR antagonism.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…In a study published after Holst’s review, Killion et al . showed that chronic GIPR agonism desensitizes GIPR activity in primary adipocytes and functions like a GIPR antagonist, favouring the GIP receptor desensitisation scenario [ 60 ]. Importantly, GIP antagonists appear able to restore the cell surface expression of GIPR [ 61 ] and therefore possess the potential to restore endogenous GIP sensitivity, a function lost in T2DM.…”

Section: Discussionmentioning

confidence: 99%

Chronic peptide-based GIP receptor inhibition exhibits modest glucose metabolic changes in mice when administered either alone or combined with GLP-1 agonism

West

Tsakmaki

Ghosh³

et al. 2021

PLoS ONE

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Combinatorial gut hormone therapy is one of the more promising strategies for identifying improved treatments for metabolic disease. Many approaches combine the established benefits of glucagon-like peptide-1 (GLP-1) agonism with one or more additional molecules with the aim of improving metabolic outcomes. Recent attention has been drawn to the glucose-dependent insulinotropic polypeptide (GIP) system due to compelling pre-clinical evidence describing the metabolic benefits of antagonising the GIP receptor (GIPR). We rationalised that benefit might be accrued from combining GIPR antagonism with GLP-1 agonism. Two GIPR peptide antagonists, GIPA-1 (mouse GIP(3–30)NH2) and GIPA-2 (NαAc-K10[γEγE-C16]-Arg18-hGIP(5–42)), were pharmacologically characterised and both exhibited potent antagonist properties. Acute in vivo administration of GIPA-1 during an oral glucose tolerance test (OGTT) had negligible effects on glucose tolerance and insulin in lean mice. In contrast, GIPA-2 impaired glucose tolerance and attenuated circulating insulin levels. A mouse model of diet-induced obesity (DIO) was used to investigate the potential metabolic benefits of chronic dosing of each antagonist, alone or in combination with liraglutide. Chronic administration studies showed expected effects of liraglutide, lowering food intake, body weight, fasting blood glucose and plasma insulin concentrations while improving glucose sensitivity, whereas delivery of either GIPR antagonist alone had negligible effects on these parameters. Interestingly, chronic dual therapy augmented insulin sensitizing effects and lowered plasma triglycerides and free-fatty acids, with more notable effects observed with GIPA-1 compared to GIPA-2. Thus, the co-administration of both a GIPR antagonist with a GLP1 agonist uncovers interesting beneficial effects on measures of insulin sensitivity, circulating lipids and certain adipose stores that seem influenced by the degree or nature of GIP receptor antagonism.

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“…Confusingly, GIP receptor antagonism has also been shown to reduce food intake [ 112 ]. Recently, Killion et al showed that, in adipose tissue, prolonged GIP receptor agonism desensitizes receptor activity, hereby mimicking functional GIP receptor antagonism [ 113 ]. It has not yet been investigated whether this is the case also in neuronal cells expressing the GIP receptor, and further studies on this topic are warranted.…”

Section: The Role Of Glp-1 and Gip In Health And Under T2dm Conditmentioning

confidence: 99%

“…Interestingly, GIP receptor agonism has been reported to show results very similar to antagonist treatment [ 116 ]. As mentioned in the previous paragraph, this paradox could be explained through agonist-induced desensitization of the adipocyte GIP receptor [ 113 ]. Genome-wide studies have linked the GIPR locus to BMI, and diminished receptor activity is associated with decreased BMI [ 80 , 116 ].…”

Section: The Role Of Glp-1 and Gip In Health And Under T2dm Conditmentioning

confidence: 99%

Incretin Hormones and Type 2 Diabetes—Mechanistic Insights and Therapeutic Approaches

Boer

Holst

2020

Biology

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Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the gut upon nutrient stimulation and regulate postprandial metabolism. These hormones are known as classical incretin hormones and are responsible for a major part of postprandial insulin release. The incretin effect is severely reduced in patients with type 2 diabetes, but it was discovered that administration of GLP-1 agonists was capable of normalizing glucose control in these patients. Over the last decades, much research has been focused on the development of incretin-based therapies for type 2 diabetes. These therapies include incretin receptor agonists and inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-4. Especially the development of diverse GLP-1 receptor agonists has shown immense success, whereas studies of GIP monotherapy in patients with type 2 diabetes have consistently been disappointing. Interestingly, both GIP-GLP-1 co-agonists and GIP receptor antagonists administered in combination with GLP-1R agonists appear to be efficient with respect to both weight loss and control of diabetes, although the molecular mechanisms behind these effects remain unknown. This review describes our current knowledge of the two incretin hormones and the development of incretin-based therapies for treatment of type 2 diabetes.

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Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism

Cited by 84 publications

References 36 publications

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

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

Chronic peptide-based GIP receptor inhibition exhibits modest glucose metabolic changes in mice when administered either alone or combined with GLP-1 agonism

Incretin Hormones and Type 2 Diabetes—Mechanistic Insights and Therapeutic Approaches

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