Aberrant alternative splicing memorized in adipose tissue macrophages impedes efferocytosis during postobesity weight loss.

Authors

Takuro Miyazaki, Akira Shiraishi, Yuki Sugiura, Eisuke Shiozawa, Seiya Mizuno, Midori Yamaguchi, Ryota Nakano, Yuki Uchida, Akira Yoshikawa, Masahiro Hosonuma, Shogo Haraguchi, Daisuke Morito, Takeshi Aoki, Toshiko Yamochi, Shotaro Kamijo, Masahiko Izumizaki, Hiroshi Shitara, Yoshitaka Taketomi, Satoru Takahashi, Honoo Satake

Published in

Science translational medicine. Volume 18. Issue 864. Pages eadv0221. Aug 26, 2026. Epub Aug 26, 2026.

Abstract

Obesity imprints an epigenetic memory in adipose tissue macrophages (ATMs), allowing proinflammatory traits to persist after weight loss. However, mechanisms by which ATMs sustain efferocytosis and influence adipose tissue mass remain unclear. Here, we demonstrate that aberrant messenger RNA splicing, caused by dysfunction of the CWC22/exon junction complex, limits efferocytosis in macrophages during postobesity weight loss. Multiomics and gene-targeting approaches revealed that 51.9% of the obesity-induced differentially spliced genes in ATMs remained altered after weight loss, identifying persistent splicing alterations as a prominent component of obesity memory, with one-quarter of these changes dependent on CWC22. Scarb1 exon skipping increased scavenger receptor class B type II (SR-BII) expression, promoting the formation of SR-BI/SR-BII heterodimers that were subsequently targeted for endoplasmic reticulum-associated degradation. This reduced surface SR-BI in macrophages, suppressed efferocytosis and inosine release from dead cells, and impaired inosine-induced lipolysis in white adipose tissue. Restoring Scarb1 splicing with an antisense oligonucleotide rescued SR-BI expression, efferocytosis, inosine availability, and fat loss in Cwc22-deficient mice. Immunohistochemical analysis of human adipose tissue specimens revealed predominant nuclear localization of CWC22 in ATMs from lean individuals, whereas this nuclear localization was markedly diminished in ATMs from obese individuals. These findings reveal that aberrant alternative splicing in macrophages underlies resistance to postobesity weight loss and suggest that splicing-targeted therapies may counteract obesity memory.

PMID:
42647594
Bibliographic data and abstract were imported from PubMed on 27 Aug 2026.

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