GIPR-Ab/GLP-1 Peptide-antibody Conjugate Requires CNS GIPRs and GLP-1Rs to Engage Anorexigenic Circuitry for Additive Weight Loss in Obese Mice
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ABSTRACT:
PROVIDER: PRJNA1243925 | ENA |
REPOSITORIES: ENA
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Project description:Glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide 1 receptor (GLP-1R) are expressed in the central nervous system (CNS) and regulate food intake. Here, we demonstrate that a peptide-antibody conjugate that blocks GIPR while simultaneously activating GLP-1R (GIPR-Ab/GLP-1) requires both CNS GIPR and CNS GLP-1R for additive effects on body weight loss in obese, primarily male, mice. Moreover, dulaglutide produces greater weight loss in CNS GIPR KO mice compared to WT mice, and the extent of weight loss achieved with dulaglutide + GIPR-Ab is attenuated in CNS GIPR KO mice. WT mice treated with GIPR-Ab/GLP-1 or CNS GIPR KO mice exhibit similar changes in gene expression related to tissue remodeling, lipid metabolism, and inflammation in white adipose tissue and liver. Moreover, GIPR-Ab/GLP-1 is detected in circumventricular organs in the brain and activates c-FOS in downstream neural substrates involved in appetite regulation. Hence, both CNS GIPR and GLP-1R signaling are required for the full effect of a GIPR-Ab/GLP-1 peptide-antibody conjugate, with loss of CNS GIPR activity potentiating the actions of GLP-1R agonism.
2025-04-29 | GSE293291 | GEO
Project description:Agonists and antagonists of the glucose-dependent insulinotropic polypeptide receptor (GIPR) enhance body weight loss induced by glucagon-like peptide-1 receptor (GLP-1R) agonism. But while GIPR agonism decreases body weight and food intake in a GLP-1R-independent manner via GABAergic GIPR+ neurons, it remains unclear whether GIPR antagonism affects energy metabolism via a similar mechanism. Here we show that the body weight and food intake reducing effects of GIPR antagonism vanish in mice with global loss of either Gipr or Glp-1r but are preserved in mice with loss of Gipr in either GABAergic or peripheral neurons. RNA-sequencing shows opposing effects of GIPR agonism and antagonism in the hindbrain, with antagonism, but not agonism, mimicking GLP-1R signaling, and with GIPR antagonism and GLP-1R agonism both regulating gene programs implicated in synaptic plasticity. Collectively, we show that GIPR agonism and antagonism decrease body weight via different mechanisms, with GIPR antagonism, unlike agonism, depending on functional GLP-1R signaling.
2025-03-12 | GSE288514 | GEO
Project description:Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor agonist, has been shown to deliver enhanced glycemic control and superior weight loss compared to a selective GLP-1 receptor (GLP-1R) agonist in patients with type 2 diabetes mellitus. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes to the therapy is not fully understood. Here, hyperinsulinemic-euglycemic clamp studies were used to show that tirzepatide is a highly effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine if GIPR agonism contributes to the insulin sensitization, we compared the effect of tirzepatide in obese wild-type and Glp-1r null mice. In the absence of GLP-1R induced weight loss, tirzepatide improved systemic insulin sensitivity by enhancing glucose disposal in WAT. To corroborate these results, chronic treatment with a long-acting GIPR agonist (LAGIPRA) was also found to enhance insulin sensitivity by increasing insulin stimulated glucose uptake in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched chain amino and keto acids in the circulation. Whole-body insulin sensitization was associated with pronounced upregulation of genes associated with the catabolism of glucose, lipid and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual GIP and GLP-1 receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.
2021-04-29 | GSE173522 | GEO
Project description:The aim is to compare gene expression profiles of Gipr–/– mice testes with those of Gipr+/+ mice testes.
2016-09-30 | GSE72504 | GEO
Project description:Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signalling is critical for GIP-based therapeutics to lower body weight, but pathways leveraged by GIPR agonism pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC)—brain regions critical to the control of energy balance. Hypothalamic expression of Gipr expression was not necessary for the synergistic effect of GIPR/ agonism combined with GLP-1R co-agonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (SAGIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to the parabrachial nucleus and paraventricular hypothalamic nucleusdistal brain regions. ScRNAseq and FISH analysis showed that Gipr neurons in the NTS and AP Gipr neurons were transcriptomically distinct. Peripherally-dosed fluorescent GIPR agonists (GIPRAs) revealed that GIPRA access was restricted to circumventricular organs in the CNS. Together tThese data demonstrate that while the hypothalamus, AP and NTS are key sites for Gipr expression, these subpopulations of Gipr neurons in the hypothalamus, AP and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility to peripherally administered GIPRAs, and the appetite controlling pathways they employ. These results highlight the heterogeneity of the central GIPR signalling axis, and suggest that studies aimed at understandinginto the effects of GIP pharmacology on feeding behaviour should consider the interplay of multiple regulatory pathways.
2023-04-07 | GSE228192 | GEO
Project description:The peroxisome proliferator-activated receptors alpha and gamma (PPAR?/?) play important roles in the regulation of energy, lipid and glucose metabolism. Drugs targeting these proteins such as Fibrates and TZDs have both shown beneficial cardiovascular effects in clinical trials, which together with their complementary action on glucose and lipid metabolism spurred the development of PPAR?/? dual-agonists (Glitazars) for the treatment of type-2 diabetes (T2D) and dyslipidemia. While effectively improving glucose and lipid metabolism in clinical trials, the development of many Glitazars was terminated due to unfavorable effects on the cardiovascular and/or renal system. Here we evaluate a single molecule conjugate of the PPAR?/? dual-agonist Tesaglitazar covalently attached to the incretin hormone glucagon-like peptide-1 receptor agonist (GLP-1RA). We hypothesized that GLP-1-mediated delivery of Tesaglitazar as well as synergism between the two agents would lead to overal beneficial effects and decrease the TZD risk profile.
2022-10-07 | PXD033653 | Pride
Project description:Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) co-agonism provide an improved therapeutic profile in individuals with T2D and obesity when compared with selective GLP-1R agonism. While the metabolic benefits of GLP-1R agonism are established, whether GIPR activation impacts weight loss through peripheral mechanisms is yet to be fully defined. Here, we generated a mouse model of GIPR induction exclusively in the adipocyte. We show that GIPR induction in the fat cell protects mice from diet-induced obesity and triggers profound weight loss (~35%) in an obese setting. Adipose GIPR further increases lipid oxidation, thermogenesis and energy expenditure. Mechanistically, we demonstrate that GIPR induction activates SERCA-mediated futile calcium cycling in the adipocyte. GIPR activation further triggers a metabolic memory effect, which maintains weight loss after the transgene has been switched off, highlighting a unique aspect in adipocyte biology. Collectively, we present a mechanism of peripheral GIPR action in adipose tissue, which exerts beneficial metabolic effects on body weight and energy balance.
2025-01-07 | GSE276975 | GEO
Project description:We purified Gipr-expressing cells from mouse hypothalamus by FACS and identified cell types distinguished by transcripts.
2022-04-27 | GSE199215 | GEO
Project description:We purified Gipr-expressing cells from mouse hypothalamus by FACS and identified cell types distinguished by transcripts.
2022-04-27 | GSE199036 | GEO
Project description:ENGAGE Transcriptomics Flagship
| PRJEB3108 | ENA