Last update 01 Nov 2024

GLP-1R x LEPR

Last update 01 Nov 2024

Basic Info

Related Targets

GLP-1RLEPR

Drugs associated with GLP-1R x LEPR

GLP1-Fc-Leptin

Target

GLP-1R x LEPR

Mechanism

GLP-1R agonists [+1]

Active Org.-

Originator Org.

Amprotein Corp.

Active Indication-

Inactive Indication

Diabetes Mellitus [+1]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GLP-1R x LEPR

100 Translational Medicine associated with GLP-1R x LEPR

0 Patents (Medical) associated with GLP-1R x LEPR

Literatures (Medical) associated with GLP-1R x LEPR

01 May 2024·Molecular Metabolism

Loss of GIPR in LEPR cells impairs glucose control by GIP and GIP:GLP-1 co-agonism without affecting body weight and food intake in mice

Article

Author: Hofmann, Susanna M ; Cota, Perla ; Maity, Gandhari ; Liskiewicz, Daniela ; Bakhti, Mostafa ; Pathak, Ekta ; Liu, Xue ; Novikoff, Aaron ; Finan, Brian ; Garcia-Caceres, Cristina ; Sterr, Michael ; Liskiewicz, Arkadiusz ; Czarnecki, Oliver ; Grandl, Gerald ; Müller, Timo D ; Parlee, Sebastian ; Khalil, Ahmed ; Ussar, Siegfried ; Tschöp, Matthias H ; Zhang, Qian ; Bastidas-Ponce, Aimée ; Bernecker, Miriam ; Pfluger, Paul T ; Gutgesell, Robert ; Akindehin, Seun ; DiMarchi, Richard ; Schriever, Sonja C ; Lickert, Heiko ; Kang, Lingru ; Douros, Jonathan D ; Drucker, Daniel J

OBJECTIVEThe glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely unknown. Here, we assessed whether GIP regulates body weight and glucose control via GIPR signaling in cells that express the leptin receptor (Lepr).METHODSHypothalamic, hindbrain, and pancreatic co-expression of Gipr and Lepr was assessed using single cell RNAseq analysis. Mice with deletion of Gipr in Lepr cells were generated and metabolically characterized for alterations in diet-induced obesity (DIO), glucose control and leptin sensitivity. Long-acting single- and dual-agonists at GIPR and GLP-1R were further used to assess drug effects on energy and glucose metabolism in DIO wildtype (WT) and Lepr-Gipr knock-out (KO) mice.RESULTSGipr and Lepr show strong co-expression in the pancreas, but not in the hypothalamus and hindbrain. DIO Lepr-Gipr KO mice are indistinguishable from WT controls related to body weight, food intake and diet-induced leptin resistance. Acyl-GIP and the GIPR:GLP-1R co-agonist MAR709 remain fully efficacious to decrease body weight and food intake in DIO Lepr-Gipr KO mice. Consistent with the demonstration that Gipr and Lepr highly co-localize in the endocrine pancreas, including the β-cells, we find the superior glycemic effect of GIPR:GLP-1R co-agonism over single GLP-1R agonism to vanish in Lepr-Gipr KO mice.CONCLUSIONSGIPR signaling in cells/neurons that express the leptin receptor is not implicated in the control of body weight or food intake, but is of crucial importance for the superior glycemic effects of GIPR:GLP-1R co-agonism relative to single GLP-1R agonism.

02 Oct 2023·The Journal of clinical investigation

Suppression of food intake by Glp1r/Lepr-coexpressing neurons prevents obesity in mouse models.

Article

Author: Myers, Martin G ; Polex-Wolf, Joseph ; Kirigiti, Melissa A ; Affinati, Alison H ; Olson, David P ; Knudsen, Lotte Bjerre ; Lindsley, Sarah R ; Rupp, Alan C ; Kievit, Paul ; Tomlinson, Abigail J ; Li, Chien ; Yacawych, Warren T ; MacKenzie, Alexander ; Seeley, Randy J ; True, Cadence ; Duensing, Allison M

The adipose-derived hormone leptin acts via its receptor (LepRb) in the brain to control energy balance. A potentially unidentified population of GABAergic hypothalamic LepRb neurons plays key roles in the restraint of food intake and body weight by leptin. To identify markers for candidate populations of LepRb neurons in an unbiased manner, we performed single-nucleus RNA-Seq of enriched mouse hypothalamic LepRb cells, identifying several previously unrecognized populations of hypothalamic LepRb neurons. Many of these populations displayed strong conservation across species, including GABAergic Glp1r-expressing LepRb (LepRbGlp1r) neurons, which expressed more Lepr than other LepRb cell populations. Ablating Lepr from LepRbGlp1r cells provoked hyperphagic obesity without impairing energy expenditure. Similarly, improvements in energy balance caused by Lepr reactivation in GABA neurons of otherwise Lepr-null mice required Lepr expression in GABAergic Glp1r-expressing neurons. Furthermore, restoration of Glp1r expression in LepRbGlp1r neurons in otherwise Glp1r-null mice enabled food intake suppression by the GLP1R agonist, liraglutide. Thus, the conserved GABAergic LepRbGlp1r neuron population plays crucial roles in the suppression of food intake by leptin and GLP1R agonists.

01 May 2023·Asian Journal of Andrology

The protective effects and underlying mechanisms of dapagliflozin on diabetes-induced testicular dysfunction

Article

Author: Luo, Zhi-Chao ; Jiang, Hui ; Cao, Ya-Lei ; Wei, Tian-Jiao ; Zhang, Zhe ; Jin, Zi-Run ; Wei, Rui ; Jiang, Ya-Fei

Male diabetic individuals present a marked impairment in fertility; however, knowledge regarding the pathogenic mechanisms and therapeutic strategies is unsatisfactory. The new hypoglycemic drug dapagliflozin has shown certain benefits, such as decreasing the risk of cardiovascular and renal events in patients with diabetes. Even so, until now, the effects and underlying mechanisms of dapagliflozin on diabetic male infertility have awaited clarification. Here, we found that dapagliflozin lowered blood glucose levels, alleviated seminiferous tubule destruction, and increased sperm concentrations and motility in leptin receptor-deficient diabetic db/db mice. Moreover, the glucagon-like peptide-1 receptor (GLP-1R) antagonist exendin (9–39) had no effect on glucose levels but reversed the protective effects of dapagliflozin on testicular structure and sperm quality in db/db mice. We also found that dapagliflozin inhibited the testicular apoptotic process by upregulating the expression of the antiapoptotic protein B-cell lymphoma 2 (BCL2) and X-linked inhibitor of apoptosis protein (XIAP) and inhibiting oxidative stress by enhancing the antioxidant status, including total antioxidant capacity, total superoxide dismutase (SOD) activity, and glutathione peroxidase (GPx) activity, as well as decreasing the level of 4-hydroxynonenal (4-HNE). Exendin (9–39) administration partially reversed these effects. Furthermore, dapagliflozin upregulated the glucagon-like peptide-1 (GLP-1) level in plasma and GLP-1R expression by promoting AKT8 virus oncogene cellular homolog (Akt) phosphorylation in testicular tissue. Exendin (9–39) partially inhibited Akt phosphorylation. These results suggest that dapagliflozin protects against diabetes-induced spermatogenic dysfunction via activation of the GLP-1R/phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Our results indicate the potential effects of dapagliflozin against diabetes-induced spermatogenic dysfunction.

Analysis

Perform a panoramic analysis of this field.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis