Introduction
 

The INHBE gene, officially named Inhibin Subunit Beta E, is located on human chromosome 12q13.3 and encodes a secreted protein belonging to the TGF-β superfamily. Traditionally, due to its sequence homology with the inhibin/activin family, it was long speculated to play a role in reproduction and development. However, several recent landmark genetic studies have rewritten its story, redefining it as a core target in the field of metabolic regulation.
 

Core Function: The Hub of the "Liver-Fat Axis," Regulating Systemic Energy Allocation
 

INHBE exhibits exceptionally high liver-specific expression in humans. The encoded βE subunit forms homodimers within hepatocytes and is secreted into the bloodstream as the hepatokine activin E. Activin E does not act on the liver itself but functions as a long-range endocrine signaling molecule, specifically targeting white adipose tissue via the circulation, forming a clear "liver-fat axis."
 

The core function of INHBE revolves around the precise regulation of "lipolysis and energy balance," primarily mediated through a signaling pathway from the liver to adipose tissue—the liver-fat axis. Under physiological conditions, moderately expressed INHBE produces activin E. This hepatokine enters the circulatory system, specifically binds to the ACVR1C receptor on adipocyte surfaces, and initiates downstream signal transduction.
 

Activin E binding to the ACVR1C receptor on adipocyte membranes activates the intracellular SMAD2/3 signaling pathway. This pathway translocates to the nucleus and inhibits the activity of the core metabolic transcription factor PPARγ. Reduced PPARγ activity leads to decreased expression of several key downstream genes that promote lipolysis, thereby physiologically inhibiting fat mobilization and promoting energy storage. This pathway functions as a negative feedback regulatory mechanism for maintaining energy homeostasis under physiological conditions. However, under pathological conditions (e.g., INHBE overexpression due to overnutrition), it can lead to excessive signaling, causing sustained and potent inhibition of lipolysis. This directly drives visceral fat accumulation, insulin resistance, and other metabolic disorders, ultimately promoting the development of diseases like obesity and type 2 diabetes.

Figure source: Wave Life Sciences Ltd. (2026, January 13).
 

Association with Core Metabolic Diseases:
 

1.Abdominal Obesity and Metabolic Syndrome:​ INHBE is a key driver of abdominal obesity and metabolic syndrome. The study "Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity" (Nature Communications, 2022) shows that its loss-of-function variants can significantly reduce waist-to-hip ratio (decrease abdominal fat) and improve metabolic markers like triglycerides and HDL-C. Mechanistically, in obesity, hepatic INHBE is overexpressed, secreting excess activin E, which continuously inhibits lipolysis via the liver-fat axis, particularly leading to visceral fat accumulation. Inflammatory factors released by visceral fat induce insulin resistance, systemically promoting the development of metabolic syndrome, type 2 diabetes, and cardiovascular diseases.
 

2.Non-alcoholic Fatty Liver Disease (NAFLD):​ The relationship between INHBE and NAFLD is complex. In animal models, INHBE deficiency leads to enhanced lipolysis, with fatty acids flooding the liver and inducing steatosis. Clinically, NAFLD patients often exhibit upregulated INHBE expression, which positively correlates with insulin resistance, suggesting it can serve as a marker of metabolic dysregulation. Targeting INHBE inhibition may indirectly improve hepatic metabolism by reducing visceral fat, but more clinical evidence is needed to support its direct efficacy for NAFLD.
 

3.Diabetes:​ INHBE is a key molecular hub linking obesity and type 2 diabetes. Human genetics studies clearly show that its loss-of-function variants reduce the risk of developing diabetes. Mendelian randomization analysis has confirmed the causal chain: "INHBE inhibition → reduced abdominal fat accumulation → reduced T2D risk." At the molecular level, overactivation of the INHBE/activin E signaling pathway drives abnormal visceral fat accumulation and systemic insulin resistance—the core pathophysiological basis of type 2 diabetes—by inhibiting lipolysis in adipose tissue.
 

Mouse Models:
 

INHBE KO Mice:​ Complete knockout of the INHBEgene, used to validate the efficacy of INHBE as a therapeutic target. This model often exhibits improved fat metabolism, reduced abdominal obesity, and enhanced insulin sensitivity.
 

INHBE Humanized Mice:​ The mouse INHBEgene is replaced with the human gene, leading to the expression of human INHBE protein. This model is a key tool in preclinical research for evaluating the pharmacokinetics, pharmacodynamics, and safety of drugs targeting human INHBE.
 

hINHBE/hINHBC Double Humanized Mice:​ Both INHBEand INHBCgenes are humanized, comprehensively simulating signaling pathways in a human physiological environment. This model is used for in-depth investigation of the regulatory mechanisms of the activin E/INHBE axis on fat distribution, dyslipidemia, and non-alcoholic fatty liver.
 

Supporting Mechanism Research and Drug Development
 

Gene therapy offers hope for common diseases, but its development and validation rely heavily on animal model support. MingCeler Biotech, leveraging its self-developed TurboMice™ technology, has developed multiple disease mouse models. The TurboMice™ technology overcomes the technical challenges of long mouse model generation cycles and low success rates for complex models, enabling editing at almost any target gene locus. Complete homozygous gene-edited mouse models can be prepared directly from embryonic stem cells in as little as two months.
 

MingCeler Biotech​ can customize various INHBE-related mouse models according to client needs, such as INHBE KO mice, INHBE humanized mice, and hINHBE/hINHBC double humanized mice. Inquiries are welcome.
 

References:
 

1.Hashimoto O, Funaba M, Sekiyama K, Doi S, Shindo D, Satoh R, Itoi H, Oiwa H, Morita M, Suzuki C, Sugiyama M, Yamakawa N, Takada H, Matsumura S, Inoue K, Oyadomari S, Sugino H, Kurisaki A. Activin E Controls Energy Homeostasis in Both Brown and White Adipose Tissues as a Hepatokine. Cell Rep. 2018 Oct 30;25(5):1193-1203. doi: 10.1016/j.celrep.2018.10.008. PMID: 30380411.

2.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. doi: 10.1073/pnas.2309967120. Epub 2023 Jul 31. PMID: 37523551; PMCID: PMC10410708.

3.Wave Life Sciences Ltd. (2026, January 13). [Presentation]. 44th Annual J.P. Morgan Healthcare Conference, San Francisco, CA.

4.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. doi: 10.1038/s41467-022-31757-8. PMID: 35896531; PMCID: PMC9329324.