INHBE, encoding the hepatokine activin E, is a gene of significance in energy metabolism and fat distribution [1,2,4,5]. It is involved in the liver-adipose inter-organ communication pathway, with activin E playing a role in suppressing adipose lipolysis in response to elevated serum fatty acids [4]. This gene is also associated with metabolic diseases such as abdominal obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) [1,2,3].

In gene-knockout studies, genetic ablation of Inhbe in mice increased fasting circulating non-esterified fatty acids (NEFA) and hepatic triglyceride accumulation [4]. Loss of Inhbe or its receptor-encoding gene ACVR1C in mice increased fat utilization and lowered adiposity, indicating a role in governing body shape and energy metabolism [5]. In contrast, overexpression of Activin E in mice suppressed adipose lipolysis and reduced serum free fatty acid (FFA) levels [4]. Disrupting the Inhbe-related Activin E-ALK7 signaling axis in Inhbe KO mice reduced adiposity but caused hepatic steatosis and insulin resistance [4].

In conclusion, Inhbe, through its encoded activin E, is a critical regulator in the liver-adipose signaling axis for metabolic homeostasis. Inhbe KO mouse models have revealed its role in regulating adipose lipolysis, fat utilization, and adiposity, which are closely related to metabolic diseases like abdominal obesity, type 2 diabetes, and NAFLD [1,2,3,4,5].

References:

1. Deaton, Aimee M, Dubey, Aditi, Ward, Lucas D, Vaishnaw, Akshay K, Nioi, Paul. 2022. Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity. In Nature communications, 13, 4319. doi:10.1038/s41467-022-31757-8. https://pubmed.ncbi.nlm.nih.gov/35896531/

2. Akbari, Parsa, Sosina, Olukayode A, Bovijn, Jonas, Verweij, Niek, Lotta, Luca A. 2022. Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes. In Nature communications, 13, 4844. doi:10.1038/s41467-022-32398-7. https://pubmed.ncbi.nlm.nih.gov/35999217/

3. Cao, Jiali, Zhong, Qiangqiang, Huang, Yumei, Wang, Ziwen, Xiong, Zhifan. 2023. Identification and validation of INHBE and P4HA1 as hub genes in non-alcoholic fatty liver disease. In Biochemical and biophysical research communications, 686, 149180. doi:10.1016/j.bbrc.2023.149180. https://pubmed.ncbi.nlm.nih.gov/37922570/

4. Griffin, John D, Buxton, Joanne M, Culver, Jeffrey A, Bence, Kendra K, Birnbaum, Morris J. 2023. Hepatic Activin E mediates liver-adipose inter-organ communication, suppressing adipose lipolysis in response to elevated serum fatty acids. In Molecular metabolism, 78, 101830. doi:10.1016/j.molmet.2023.101830. https://pubmed.ncbi.nlm.nih.gov/38787338/

5. Adam, Rene C, Pryce, Dwaine S, Lee, Joseph S, Sleeman, Mark W, Gusarova, Viktoria. 2023. Activin E-ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice. In Proceedings of the National Academy of Sciences of the United States of America, 120, e2309967120. doi:10.1073/pnas.2309967120. https://pubmed.ncbi.nlm.nih.gov/37523551/