huINHBE-6xHIS Mouse
Product Name
huINHBE-6xHIS Mouse
Product ID
C002013
Strain Name
C57BL/6NCya-Inhbeem2(huINHBE-6xHIS)/Cya
Backgroud
C57BL/6NCya
Status
When using this mouse strain in a publication, please cite “huINHBE-6xHIS Mouse (Catalog C002013) were purchased from Cyagen.”
Product Type
Age
Genotype
Sex
Quantity
Gene Name
INHBE
Gene Alias
--
NCBI ID
Chromosome
Chr 12 (Human)
MGI ID
Datasheet
Strain Description
Inhibin βE subunit (INHBE) is a member of the transforming growth factor-β (TGF-β) superfamily and is highly specifically expressed in hepatocytes. The INHBE precursor protein is proteolytically processed to generate the mature inhibin βE subunit, which is involved in various biological processes, including cell proliferation, apoptosis, immune regulation, and hormone secretion. During obesity- and diabetes-associated metabolic disorders, INHBE expression is altered and participates in the regulation of lipid metabolism, adipose storage, and insulin sensitivity. Studies have shown that hepatic INHBE expression is positively correlated with insulin resistance and body mass index (BMI) in humans, suggesting that INHBE may function as a hepatokine involved in systemic metabolic regulation under obesity-associated insulin-resistant conditions [1]. In 2022, studies from Alnylam Pharmaceuticals and the Regeneron Genetics Center (RGC) revealed a close relationship between INHBE and adipose regulation. Research demonstrated that rare loss-of-function (LOF) variants in INHBE may promote healthier adipose storage patterns, improve metabolic profiles, and reduce the risk of obesity-associated inflammation, dyslipidemia, and type 2 diabetes mellitus (T2D). Patients carrying such variants exhibited improved fat distribution, reduced abdominal adiposity, better metabolic health, and significantly decreased risks of cardiovascular disease and T2D [2-4]. These findings indicate that INHBE is a liver-specific negative regulator of adipose storage. Suppression of INHBE expression may represent a potential therapeutic strategy for metabolic disorders associated with abnormal fat distribution and storage. Therefore, several small nucleic acid pharmaceutical companies, including Alnylam Pharmaceuticals, Arrowhead Pharmaceuticals, and Wave Life Sciences, are currently developing RNA interference (RNAi)-based therapeutics targeting INHBE for the treatment of obesity and related metabolic diseases [5-7].
huINHBE-6xHIS mice were generated based on the huINHBE humanized model (Catalog No.: C001533). In this model, the genomic region from the start codon to the 3’UTR of mouse Inhbe was replaced with the corresponding region of human INHBE, and a 6xHIS tag sequence was inserted upstream of the stop codon in exon 2 of the human INHBE gene. This modification enables specific detection of human INHBE protein using His-tag antibodies. huINHBE-6xHIS mice can be used for obesity and metabolic disease research, preclinical evaluation of human INHBE-targeted therapeutics, investigation of liver-adipose tissue communication mechanisms, studies of type 2 diabetes mellitus (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), and validation of human INHBE expression regulation and function.
Reference
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.
Arrowhead Pharmaceuticals. (2024). Arrowhead Pharmaceuticals Reports Fiscal 2024 First Quarter Results. Retrieved April 5, 2024, from https://arrowheadpharma.com/news-press/arrowhead-pharmaceuticals-reports-fiscal-2024-first-quarter-results-2/
Alnylam Pharmaceuticals. (2024). Harnessing Human Genetics to Power the Next Wave of RNAi Therapeutics. Retrieved April 5, 2024, from https://news.alnylam.com/rnai/articles/harnessing-human-genetics-power-next-wave-rnai-therapeutics
Wave Life Sciences. (2024). Research and Development. Retrieved April 5, 2024, from https://wavelifesciences.com/pipeline/research-and-development/
Strain Strategy
huINHBE-6xHIS mice were generated based on the huINHBE humanized model (Catalog No.: C001533). The sequences from the start codon to 3'UTR of mouse Inhbe were replaced with the sequences from the start codon to 3'UTR of human INHBE, and a 6xHIS tag sequence was inserted upstream of the stop codon in exon 2 of the human INHBE gene.
Figure 1. Gene editing strategy of huINHBE-6xHIS mice.
Application Area
Obesity and metabolic disease research: Used to investigate the pathological mechanisms underlying abnormal adipose distribution, energy metabolism imbalance, and related metabolic disorders.
Development of human INHBE-targeted therapeutics: Used as a preclinical pharmacological evaluation platform to assess the efficacy of human INHBE-targeted nucleic acid therapeutics (such as siRNA) or other therapeutic candidates.
Investigation of liver-adipose tissue communication mechanisms: Used to explore the role of INHBE as a hepatokine in regulating adipose metabolism and systemic energy homeostasis.
Type 2 diabetes mellitus (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) research: Used to model and investigate the progression of metabolic disorders, including insulin resistance and hepatic steatosis, as well as potential intervention strategies.
Human INHBE expression regulation and functional validation: Human INHBE expression levels can be evaluated using Western blot and qPCR assays to validate the metabolic regulatory function of INHBE under fasting and feeding conditions.
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