huINHBC/huINHBE Mouse
Product Name
huINHBC/huINHBE Mouse
Product ID
C001931
Strain Name
C57BL/6NCya-Inhbctm1(hINHBC)Inhbetm2(hINHBE)/Cya
Backgroud
C57BL/6NCya
Status
When using this mouse strain in a publication, please cite “huINHBC/huINHBE Mouse (Catalog C001931) were purchased from Cyagen.”
Product Type
Age
Genotype
Sex
Quantity
Gene Alias
IHBC
Chromosome
Chr 12, Chr 12
MGI ID
Datasheet
Strain Description
The inhibin βC subunit (INHBC) is a member of the transforming growth factor-β (TGF-β) superfamily. Its encoded precursor protein undergoes hydrolytic processing to form homodimers or heterodimeric activin complexes with βA/βB subunits, which are involved in inhibiting the activin A signaling pathway and regulating multiple physiological processes. INHBC is abundantly expressed in the liver and also participates in the regulation of hormone secretion in the reproductive system [1-2]. Studies have confirmed that circulating INHBC is associated with reduced subcutaneous fat, dyslipidemia, and increased risks of coronary artery disease (CAD) and non-alcoholic fatty liver disease (NAFLD). Meanwhile, obesity, hypertriglyceridemia, type 2 diabetes mellitus, and other conditions positively regulate plasma INHBC levels. Recombinant INHBC (Act-C) can inhibit lipolysis in adipocytes by activating the ALK7-SMAD2/3 signaling pathway, further clarifying its role in metabolic regulation [3].
The inhibin βE subunit (INHBE) is also a member of the TGF-β superfamily, with highly specific expression in hepatocytes. The precursor protein of INHBE generates the inhibin β subunit after proteolytic processing. This protein is associated with various cellular processes, including cell proliferation, apoptosis, immune response, and hormone secretion. During the development of obesity and diabetes, the expression of INHBE protein inhibits the proliferation and growth of relevant cells in the pancreas and liver. Research has found a positive correlation between INHBE expression in the liver and insulin resistance and body mass index (BMI), suggesting that INHBE may be a liver factor in altering systemic metabolic status under conditions of obesity-related insulin resistance [4]. The studies conducted by Alnylam Pharmaceuticals and the Regeneron Genetics Center (RGC), respectively, revealed the close relationship between INHBE and fat regulation. The research demonstrated that rare loss-of-function variants in INHBE may protect the liver from the impact of inflammation, abnormal blood lipids, and type 2 diabetes by promoting healthy fat storage. Patients carrying such mutations exhibit more normal fat distribution, significantly reduced abdominal fat, improved metabolic conditions, and a decreased risk of cardiovascular diseases and type 2 diabetes [5-7]. These findings suggest that INHBE is a liver-specific negative regulator of fat storage. Inhibiting the expression of INHBE genes and proteins may be a promising strategy for treating metabolic disorders associated with improper fat distribution and storage.
The huINHBC/huINHBE mouse is a dual-gene humanized model established via gene editing technology. In this model, the sequences from upstream of the mouse Inhbc exon 1 to the mouse Inhbe 3'UTR were replaced with the sequences from upstream of the human INHBC exon 1 to 3'UTR of the human INHBE. This model can be utilized for investigating the mechanisms and therapeutic approaches of fat distribution and storage, dyslipidemia, CAD, NAFLD, as well as for the development of INHBC/INHBE-targeted drugs.
Reference
Schmitt J, Hötten G, Jenkins NA, Gilbert DJ, Copeland NG, Pohl J, Schrewe H. Structure, chromosomal localization, and expression analysis of the mouse inhibin/activin beta C (Inhbc) gene. Genomics. 1996 Mar 15;32(3):358-66.
Chang HM, Cheng JC, Klausen C, Taylor EL, Leung PC. Effects of recombinant activins on steroidogenesis in human granulosa-lutein cells. J Clin Endocrinol Metab. 2014 Oct;99(10):E1922-32.
Loh NY, Rosoff DB, Richmond R, Noordam R, Smith GD, Ray D, Karpe F, Lohoff FW, Christodoulides C. Bidirectional Mendelian Randomization Highlights Causal Relationships Between Circulating INHBC and Multiple Cardiometabolic Diseases and Traits. Diabetes. 2024 Dec 1;73(12):2084-2094.
Sugiyama M, Kikuchi A, Misu H, Igawa H, Ashihara M, Kushima Y, Honda K, Suzuki Y, Kawabe Y, Kaneko S, Takamura T. Inhibin βE (INHBE) is a possible insulin resistance-associated hepatokine identified by comprehensive gene expression analysis in human liver biopsy samples. PLoS One. 2018 Mar 29;13(3):e0194798.
Akbari P, Sosina OA, Bovijn J, Landheer K, Nielsen JB, Kim M, Aykul S, De T, Haas ME, Hindy G, Lin N, Dinsmore IR, Luo JZ, Hectors S, Geraghty B, Germino M, Panagis L, Parasoglou P, Walls JR, Halasz G, Atwal GS; Regeneron Genetics Center; DiscovEHR Collaboration; Jones M, LeBlanc MG, Still CD, Carey DJ, Giontella A, Orho-Melander M, Berumen J, Kuri-Morales P, Alegre-Díaz J, Torres JM, Emberson JR, Collins R, Rader DJ, Zambrowicz B, Murphy AJ, Balasubramanian S, Overton JD, Reid JG, Shuldiner AR, Cantor M, Abecasis GR, Ferreira MAR, Sleeman MW, Gusarova V, Altarejos J, Harris C, Economides AN, Idone V, Karalis K, Della Gatta G, Mirshahi T, Yancopoulos GD, Melander O, Marchini J, Tapia-Conyer R, Locke AE, Baras A, Verweij N, Lotta LA. Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes. Nat Commun. 2022 Aug 23;13(1):4844.
Deaton AM, Dubey A, Ward LD, Dornbos P, Flannick J; AMP-T2D-GENES Consortium; Yee E, Ticau S, Noetzli L, Parker MM, Hoffing RA, Willis C, Plekan ME, Holleman AM, Hinkle G, Fitzgerald K, Vaishnaw AK, Nioi P. Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity. Nat Commun. 2022 Jul 27;13(1):4319.
Adam RC, Pryce DS, Lee JS, Zhao Y, Mintah IJ, Min S, Halasz G, Mastaitis J, Atwal GS, Aykul S, Idone V, Economides AN, Lotta LA, Murphy AJ, Yancopoulos GD, Sleeman MW, Gusarova V. Activin E-ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice. Proc Natl Acad Sci U S A. 2023 Aug 8;120(32):e2309967120.
Strain Strategy
The sequences from upstream of the mouse Inhbc exon 1 to the mouse Inhbe 3'UTR were replaced with the sequences from upstream of the human INHBC exon 1 to 3'UTR of the human INHBE. The 3xFLAG tag was inserted upstream of the TAG stop codon of human INHBC gene, and the 6xHis tag was inserted upstream of the TAG stop codon of human INHBE gene.
Figure 1. Gene editing strategy for huINHBC/huINHBE mice.
Application Area
Screening, research, and pre-clinical evaluation of INHBC/INHBE-targeted drugs;
Research on metabolic diseases associated with obesity and improper fat distribution and storage;
Research on coronary artery disease (CAD), non-alcoholic fatty liver disease (NAFLD), etc.
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