Name: B6-hGLP-1R Mouse
Brand: サイヤジェン（Cyagen）
SKU: C001421

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B6-hGLP-1R Mouse

製品名

B6-hGLP-1R Mouse

製品ID

C001421

系統名

C57BL/6NCya-Glp1r^tm1(hGLP1R)/Cya

背景情報

C57BL/6NCya

状況

このマウス系統を論文で使用する場合は、「B6-hGLP-1R Mouse（カタログ番号C001421）はサイアジェンから購入しました。」と引用してください。

Metabolic Target Humanized Mouse Models

Fat Reduction and Muscle Gain

Obesity and Diabetes Mellitus

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遺伝子型

性別

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Metabolic Target Humanized Mouse Models

Fat Reduction and Muscle Gain

Obesity and Diabetes Mellitus

基本情報

検証 Data

系統詳細

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].

B6-hGLP-1R mice are a model of mouse Glp1r gene humanization, in which the sequences encoding the seven-transmembrane (7TM) structural domain and the larger extracellular structural domain of the human GLP1R gene were inserted into the mouse Glp1r gene sequence using gene editing technology. This model expresses the key functional regions of the human GLP-1R protein while preserving the signal peptide and 3’UTR region of mouse GLp1r. It can be used to study the pathogenesis of various metabolic diseases, such as obesity and type II diabetes, as well as for screening in GLP-1RA drug development. Homozygous B6-hGLP-1R mice are viable and fertile.

参考文献

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.

Saxena AR, Gorman DN, Esquejo RM, Bergman A, Chidsey K, Buckeridge C, Griffith DA, Kim AM. Danuglipron (PF-06882961) in type 2 diabetes: a randomized, placebo-controlled, multiple ascending-dose phase 1 trial. Nat Med. 2021 Jun;27(6):1079-1087.

Christou GA, Katsiki N, Blundell J, Fruhbeck G, Kiortsis DN. Semaglutide as a promising antiobesity drug. Obes Rev. 2019 Jun;20(6):805-815.

Pratt E, Ma X, Liu R, Robins D, Haupt A, Coskun T, Sloop KW, Benson C. Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1a, blinded, placebo-controlled, randomized, single- and multiple-ascending-dose study in healthy participants. Diabetes Obes Metab. 2023 Sep;25(9):2634-2641.

系統作製戦略

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 1. Gene editing strategy for B6-hGLP-1R mice.

適用分野

Investigation of the pathogenesis of obesity and type 2 diabetes;

Development and screening of drugs 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.

検証 Data

1. Expression of the human GLP-1R gene and protein

(A) qRT-PCR results showed that the human GLP-1R gene was significantly expressed in the lungs, large intestine, and brain of B6-hGLP-1R mice, while no human GLP-1R gene expression was detected in the lungs, large intestine*, and brain of WT mice (*p<0.05, **p<0.01).

(B) Western blot results showed that GLP-1R protein was strongly expressed in the pancreas of B6-hGLP-1R mice, and weakly expressed in the lungs**.

Figure 2. Human GLP1R gene and protein expression in different tissues of C57BL6 wild-type (WT) and B6-hGLP-1R mice at 6 weeks of age. *The expression level of this gene in the intestine is relatively low, and the sequence homology between human and mouse genes is high. The amplified product in the WT group may not be a human gene band. **The GLP-1R antibody used for detection is a cross-reacting antibody for human and mouse.

2. Immunohistochemistry (IHC) of pancreatic tissue

Immunohistochemical (IHC) staining of the pancreas revealed strong GLP-1R protein expression in islets of B6-hGLP-1R mice*.

Figure 3. Distribution of human GLP-1R protein in the pancreas of 6-week-old wild-type (WT) and homozygous (HO) B6-hGLP-1R mice. *The GLP-1R antibody used for detection is a cross-reacting antibody for human and mouse.

3. Immunofluorescence (IF) staining of pancreatic tissue

Immunofluorescent (IF) staining of the pancreas revealed strong GLP-1R protein expression in islets of B6-hGLP-1R mice*.

Figure 4. Distribution of human GLP-1R protein in the pancreas of 6-week-old wild-type (WT) and homozygous (HO) B6-hGLP-1R mice. *The GLP-1R antibody used for detection is a cross-reacting antibody for human and mouse.

4. Pharmacodynamics (PD) of PF-06882961 in B6-hGLP-1R mice

(A~D). Under a control diet (CD), PF-06882961 effectively reduced blood glucose in B6-hGLP-1R mice compared to wild-type mice, as evidenced by the significantly reduced area under the curve (AUC) for the Intraperitoneal glucose tolerance test (IPGTT) (A~B) and food intake (C~D).

(E~H). High-fat diet (HFD) effectively induced obesity in B6-hGLP-1R and wild-type mice (E~F), and PF-06882961 significantly reduced AUC for IPGTT in B6-hGLP-1R mice (G~H), indicating that PF-06882961 can improve glucose tolerance in obese B6-hGLP-1R mice. Since PF-06882961 is a human GLP-1R-specific agonist, the above results suggest that B6-hGLP-1R mice successfully express human GLP-1R protein and interact with PF-06882961 to achieve significant blood glucose lowering (8-week-old male mice, n=6, *p<0.05; **p<0.01; ***p<0.001).

Figure 5. PF-06882961* significantly reduced blood glucose in B6-hGLP-1R mice under a control diet (CD) and high-fat diet (HFD). *PF-06882961 is a non-peptide GLP-1R agonist (GLP-1RA) that activates the canonical G protein signaling pathway only in GLP-1Rs with the Trp33ECD structure^[6].

5. Pharmacodynamics (PD) of Semaglutide in B6-hGLP-1R mice

(A). After 12 weeks of HFD feeding, Semaglutide (30 nmol/kg, twice weekly, subcutaneous injection, male mice, 30-90 min before the start of the dark cycle) was administered to B6-hGLP-1R mice. The body weight, food intake, blood glucose levels before and after administration, and AUC for IPGTT were regularly monitored.

(B~E). Compared to the control group, Semaglutide administration significantly reduced the body weight (B), random blood glucose (C), and food intake of B6-hGLP-1R mice (D~E).

(F~G). Semaglutide significantly decreased the AUC for IPGTT in B6-hGLP-1R mice, suggesting that it can improve the glucose tolerance of B6-hGLP-1R mice and exhibit good blood-glucose-lowering effects.

(H~I). Compared to wild-type and control groups, the body weight of Semaglutide-treated B6-hGLP-1R mice at the endpoint was significantly decreased.

(*p<0.05; **p<0.01; ***p<0.001)

Figure 6. Semaglutide* significantly reduced blood glucose and body weight in B6-hGLP-1R mice under a high-fat diet (HFD). *Semaglutide is a GLP-1R agonist (GLP-1RA) with a longer drug half-life^[7].

6. Pharmacodynamics (PD) of LY3502970 in B6-hGLP-1R mice

Intraperitoneal glucose tolerance test (IPGTT) was used to detect the hypoglycemic effect of LY3502970, and B6-hGLP-1R mice were treated with different doses of LY3502970 at 5 hours before the start of the detection. The results demonstrate that LY3502970 treatment leads to a significant decrease in blood glucose content in B6-hGLP-1R mice, with a markedly reduced area under the curve (AUC) in the IPGTT. This indicates that the drug improves glucose tolerance in B6-hGLP-1R mice and has a favorable blood glucose-lowering effect (****p<0.0001).

Figure 7. The LY3502970* significantly reduces blood glucose levels in 6-week-old male B6-hGLP-1R mice (Normal diet)**. *Orforglipron (LY3502970) is an orally active glucagon-like peptide-1 receptor (GLP-1R) agonist that significantly improves type 2 diabetes^[8]. **Data provided by Cyagen's client.

B6-hGLP-1R Mouse

基本情報

検証 Data

関連リソース

遺伝子名

遺伝子別名

NCBI ID

染色体

MGI ID

さらに

データシート

系統詳細

参考文献

系統作製戦略

適用分野

1. Expression of the human GLP-1R gene and protein

2. Immunohistochemistry (IHC) of pancreatic tissue

3. Immunofluorescence (IF) staining of pancreatic tissue

4. Pharmacodynamics (PD) of PF-06882961 in B6-hGLP-1R mice

5. Pharmacodynamics (PD) of Semaglutide in B6-hGLP-1R mice

6. Pharmacodynamics (PD) of LY3502970 in B6-hGLP-1R mice

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