B6-hGIPR/hGLP-1R Mouse
Product Name
B6-hGIPR/hGLP-1R Mouse
Product ID
C001599
Strain Name
C57BL/6NCya-Giprem1(hGIPR)Glp1rtm1(hGLP1R)/Cya
Backgroud
C57BL/6NCya
When using this mouse strain in a publication, please cite “B6-hGIPR/hGLP-1R Mouse (Catalog C001599) were purchased from Cyagen.”
Product Type
Age
Genotype
Sex
Quantity
Gene Alias
PGQTL2, GLP-1, GLP-1R, GLP-1-R
Chromosome
Chr 19, Chr 6
MGI ID
Datasheet
Strain Description
The Glucagon-like peptide 1 receptor (GLP1R) gene encodes a protein that belongs to the glucagon receptor subfamily of the G protein-coupled receptor B cluster [1]. This cell surface receptor protein is widely expressed in tissues such as the brain, small intestine, heart, and lungs, and plays a crucial role in insulin secretion signaling cascades by responding to GLP-1 and GLP-1 analogs. Animal model data also suggest that it has neuroprotective effects. Polymorphisms of this gene are closely associated with diabetes, making the GLP-1R protein an important drug target for the treatment of type 2 diabetes and stroke [2-3]. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are novel anti-diabetic drugs that activate GLP-1R to enhance insulin secretion, inhibit glucagon secretion, delay gastric emptying, and reduce food intake through central appetite suppression, thereby achieving blood sugar reduction and weight loss [4].
The GIPR gene encodes a G-protein-coupled receptor for gastric inhibitory polypeptide (GIP), secreted by intestinal K cells after food intake. GIP was initially discovered in intestinal extracts to inhibit gastric acid secretion and gastrin release, but it was later found to stimulate insulin release in the presence of elevated glucose levels. GIPR activation stimulates pancreatic β-cells to secrete insulin and mediates fat deposition by increasing lipoprotein lipase activity, adipogenesis, and fatty acid and glucose uptake in adipocytes. GIPR is primarily expressed in EBV-transformed lymphocytes, the stomach, and visceral adipose tissue [6]. Knockout mice for this gene exhibit elevated blood glucose levels and impaired initial insulin response following oral glucose load. Mice with disrupted Gipr expression show resistance to diet-induced obesity [7]. A deficiency in the GIPR gene is associated with type 2 diabetes and obesity. Research suggests that one of the core strategies for the next generation of T2D drugs is the production of single-peptide agonists, targeting both GLP-1R activity and the glucose-dependent insulinotropic polypeptide receptor (GIPR). GIPR involvement enhances the weight-loss effects of GLP-1-based therapies. This approach improves glycemic control and weight loss in T2D patients, highlighting the GIPR signaling axis as a promising and effective co-target [8].
The B6-hGIPR/hGLP-1R mouse is a dual humanized model for the Gipr and Glp1r genes. Using gene-editing technology, a partial coding sequence (CDS) of the human GIPR gene was inserted into the mouse Gipr gene sequence in B6-hGLP-1R mice (Catalog No.: C001421). This model expresses the functional region of the human GIPR protein while preserving the mouse signal peptide. It can be used to study the pathogenic mechanisms of metabolic diseases such as obesity and type 2 diabetes, and the development of GIPR/GLP-1R dual agonist drugs. The homozygotes are viable and fertile.
Reference
Blad CC, Tang C, Offermanns S. G protein-coupled receptors for energy metabolites as new therapeutic targets. Nat Rev Drug Discov. 2012 Aug;11(8):603-19.
Yun SP, Kam TI, Panicker N, Kim S, Oh Y, Park JS, Kwon SH, Park YJ, Karuppagounder SS, Park H, Kim S, Oh N, Kim NA, Lee S, Brahmachari S, Mao X, Lee JH, Kumar M, An D, Kang SU, Lee Y, Lee KC, Na DH, Kim D, Lee SH, Roschke VV, Liddelow SA, Mari Z, Barres BA, Dawson VL, Lee S, Dawson TM, Ko HS. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease. Nat Med. 2018 Jul;24(7):931-938.
Schonhoff AM, Harms AS. Glial GLP1R: A novel neuroprotector? Mov Disord. 2018 Dec;33(12):1877.
Andreasen CR, Andersen A, Knop FK, Vilsbøll T. Understanding the place for GLP-1RA therapy: Translating guidelines for treatment of type 2 diabetes into everyday clinical practice and patient selection. Diabetes Obes Metab. 2021 Sep;23 Suppl 3:40-52.
Laviola L, Leonardini A, Melchiorre M, Orlando MR, Peschechera A, Bortone A, Paparella D, Natalicchio A, Perrini S, Giorgino F. Glucagon-like peptide-1 counteracts oxidative stress-dependent apoptosis of human cardiac progenitor cells by inhibiting the activation of the c-Jun N-terminal protein kinase signaling pathway. Endocrinology. 2012 Dec;153(12):5770-81.
Turcot V, Lu Y, Highland HM, Schurmann C, Justice AE, Fine RS, Bradfield JP, Esko T, Giri A, Graff M, et. al. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat Genet. 2018 Jan;50(1):26-41. doi: 10.1038/s41588-017-0011-x. Epub 2017 Dec 22. Erratum in: Nat Genet. 2018 May;50(5):765-766. doi: 10.1038/s41588-018-0050-y. Erratum in: Nat Genet. 2018 May;50(5):766-767. doi: 10.1038/s41588-018-0082-3. Erratum in: Nat Genet. 2019 Jul;51(7):1191-1192. doi: 10.1038/s41588-019-0447-2.
Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K, Zhou H, Fujimoto S, Oku A, Tsuda K, Toyokuni S, Hiai H, Mizunoya W, Fushiki T, Holst JJ, Makino M, Tashita A, Kobara Y, Tsubamoto Y, Jinnouchi T, Jomori T, Seino Y. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med. 2002 Jul;8(7):738-42.
Samms RJ, Sloop KW, Gribble FM, Reimann F, Adriaenssens AE. GIPR Function in the Central Nervous System: Implications and Novel Perspectives for GIP-Based Therapies in Treating Metabolic Disorders. Diabetes. 2021 Sep;70(9):1938-1944.
Strain Strategy
Figure 1. Gene editing strategy for B6-hGLP-1R mice. Part of the exon 1 sequence and part of the intron 1 sequence in the mouse Glp1r gene were replaced with hGLP1R Exon 1~2 CDS (without signal peptide), hGLP1R Intron 2 and hGLP1R Exon 3~13 CDS - mGlp1r 3’UTR - hGH pA while retaining the gene sequence encoding the signal peptide of the mouse Glp1r protein.
Figure 2. Gene editing strategy for B6-hGIPR/hGLP-1R mice. In B6-hGLP-1R mice (Catalog No.: C001421), the exon 3 to partial intron 3 of mouse Gipr was replaced with the Exon 3~14 of Human GIPR CDS - 3'UTR of Mouse Gipr - WPRE-BGH pA. The murine signal peptide was preserved.
Application Area
Pathogenesis of obesity and type 2 diabetes;
Drug development for obesity and type 2 diabetes;
Research on other metabolic diseases, such as cardiovascular and myocardial diseases<sup> [5]</sup>;
Study of the neuroprotective effect in nervous system diseases.
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