B6-hINHBE/ob Mouse

Inhibin βE subunit (INHBE) is a member of the transforming growth factor-β (TGF-β) superfamily, highly specifically expressed in liver cells. 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 ^[1]. 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 ^[2-4]. 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 potential strategy for treating metabolic disorders related to improper fat distribution and storage. Consequently, several small nucleic acid pharmaceutical companies, including Alnylam Pharmaceuticals, Arrowhead Pharmaceuticals, and Wave Life Sciences, are currently developing RNA interference (RNAi) drugs targeting INHBE to treat obesity ^[5-7].

The leptin (LEP) gene, also known as the OB gene, encodes the leptin protein, which is secreted into the circulation by white adipocytes and plays a major role in regulating energy homeostasis. Circulating leptin binds to leptin receptors (LEPR) in the brain, activating downstream signaling pathways that inhibit feeding and promote energy expenditure. Leptin also has multiple endocrine functions and is involved in physiopathological processes such as immune and inflammatory responses, hematopoiesis, angiogenesis, reproduction, bone formation, and wound healing ^[8]. Mutations in the LEP gene and its regulatory regions lead to severe obesity and morbid obesity with hypogonadism in humans and are also associated with the development of type II diabetes ^[9].

The B6-hINHBE/ob mouse model, generated by mating B6-hINHBE mice (Catalog Number: C001533) with Lep KO (ob/ob) mice (Catalog Number: C001368), is a metabolic disease model. It can be used for research on obesity, type II diabetes, and metabolic diseases related to improper fat distribution and storage, and for the development of human INHBE-targeted therapies.