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Stabilization of insulin receptor mRNA by Star-PAP in metabolic homeostasis [ATAC-seq]

ABSTRACT: Conserved polyadenylation by poly(A) polymerases (PAPs) is essential for mRNA stability, yet its metabolic functions remain unclear. Here we identify a rare variant p.D469N (Asp469Asn) in Star-PAP present in lean individuals but absent in obese cases. Adipose-specific Star-PAP knockout mice develop progressive adipose tissue loss, hepatic steatosis, and severe insulin resistance, phenocopying human lipodystrophy. Mechanistically, Star-PAP directly binds the the insulin receptor (InsR) mRNA 3’–UTR to stabilize its transcript. Both deletion of Star-PAP and p.D469N variant decrease InsR mRNA maturation. Star-PAP deficiency impaires insulin receptor signaling and adipocyte lipid storage, while restoring InsR in adipocytes partially ameliorates the lipodystrophic phenotypes. Notably, Star-PAP deficiency disruptes acetyl-CoA homeostasis secondary to insulin signaling defects, accompanied by reduced histone acetylation at fatty acid synthesis genes. Pyruvate supplementation effectively restores acetyl-CoA levels and histone acetylation, thereby rescuing the gene expression and lipogenesis. Together, our results identify Star-PAP-mediated RNA polyadenylation as a mechanism governing adipose homeostasis, positioning Star-PAP as a key regulator of insulin receptor signaling and lipodystrophy.

ORGANISM(S): Mus musculus

PROVIDER: GSE345555 | GEO | 2026/09/08

REPOSITORIES: GEO

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

Project description:Conserved polyadenylation by poly(A) polymerases (PAPs) is essential for mRNA stability, yet its metabolic functions remain unclear. Here we identify a rare variant p.D469N (Asp469Asn) in Star-PAP present in lean individuals but absent in obese cases. Adipose-specific Star-PAP knockout mice develop progressive adipose tissue loss, hepatic steatosis, and severe insulin resistance, phenocopying human lipodystrophy. Mechanistically, Star-PAP directly binds the the insulin receptor (InsR) mRNA 3’–UTR to stabilize its transcript. Both deletion of Star-PAP and p.D469N variant decrease InsR mRNA maturation. Star-PAP deficiency impaires insulin receptor signaling and adipocyte lipid storage, while restoring InsR in adipocytes partially ameliorates the lipodystrophic phenotypes. Notably, Star-PAP deficiency disruptes acetyl-CoA homeostasis secondary to insulin signaling defects, accompanied by reduced histone acetylation at fatty acid synthesis genes. Pyruvate supplementation effectively restores acetyl-CoA levels and histone acetylation, thereby rescuing the gene expression and lipogenesis. Together, our results identify Star-PAP-mediated RNA polyadenylation as a mechanism governing adipose homeostasis, positioning Star-PAP as a key regulator of insulin receptor signaling and lipodystrophy.

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