RNA-processing enzyme Star-PAP stabilizes insulin receptor mRNA and guards fat tissue

A rare variant in an RNA-processing enzyme may help explain why some people stay lean while others accumulate fat, according to a study published in Nature Communications. The enzyme, Star-PAP, a poly(A) polymerase that adds polyadenylate tails to messenger RNA, emerged from the study as a key regulator of insulin receptor signaling and adipose tissue mass, with loss of its function producing severe metabolic disease in mice.

The researchers identified a rare variant, p.D469N (Asp469Asn), in the Star-PAP gene that was present in lean individuals but absent in obese cases. To test the enzyme's role directly, the team generated mice lacking Star-PAP specifically in adipose tissue.

Mice engineered to lack Star-PAP specifically in adipose tissue developed a striking cascade of metabolic abnormalities: progressive loss of fat tissue, fatty liver disease, and severe insulin resistance. The researchers noted that these animals phenocopy human lipodystrophy, a disorder in which the body cannot properly store fat and metabolic complications follow.

The mechanism centers on the insulin receptor transcript. Star-PAP directly binds the 3-prime untranslated region of insulin receptor mRNA and stabilizes it, ensuring the transcript matures properly. Both deletion of Star-PAP and the p.D469N variant reduced the maturation of insulin receptor mRNA, lowering production of the receptor through which insulin exerts its effects on fat cells.

Without adequate Star-PAP, insulin receptor signaling in adipocytes faltered, and the cells’ capacity to store lipid declined. Restoring the insulin receptor in adipocytes partially ameliorated the lipodystrophic phenotypes, indicating that the loss of this receptor is a central node in the disease process rather than the sole cause.

The study also uncovered a downstream metabolic consequence. Star-PAP deficiency disrupted acetyl-CoA homeostasis as a secondary effect of the insulin signaling defects, and this was accompanied by reduced histone acetylation at genes involved in fatty acid synthesis.

Notably, the researchers found a potential rescue strategy: pyruvate supplementation restored acetyl-CoA levels and histone acetylation, thereby rescuing gene expression and lipogenesis in the affected cells. This result positions an RNA-stabilizing defect as a targetable metabolic bottleneck, although the rescue was demonstrated in the study’s experimental system and further work would be needed to establish any therapeutic relevance in humans.

Together, the findings identify Star-PAP-mediated RNA polyadenylation as a mechanism governing adipose tissue mass, positioning the enzyme as a regulator of insulin receptor signaling and a candidate contributor to lipodystrophy. The work also underscores how a rare human variant, when tested in controlled animal models, can reveal an unexpected connection between mRNA maturation, chromatin modification, and whole-body metabolism.

Subject of Research: The role of the polyadenylation enzyme Star-PAP in stabilizing insulin receptor mRNA and regulating adipose tissue and metabolic homeostasis

Article Title: Stabilization of insulin receptor mRNA by Star-PAP in metabolic homeostasis

Article References: Chen, N., Zhao, Y., Chen, Y., Tong, M., Gu, W., Hong, J., Liu, Y., Yin, N., Lu, P., Ni, M., Zhang, Z., Li, D., Chen, Y., Zhao, S., Gao, A., Zheng, J., Cao, M., Cui, B., Bi, Y., … Wang, J. (2026). Stabilization of insulin receptor mRNA by Star-PAP in metabolic homeostasis. Nature Communications. https://doi.org/10.1038/s41467-026-78465-1

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78465-1

Keywords: Star-PAP, polyadenylation, insulin receptor, mRNA stability, lipodystrophy, adipose tissue, insulin resistance, hepatic steatosis, acetyl-CoA, histone acetylation, rare variant, metabolic homeostasis