Sirt3 deficiency impairs AMPK–Acc1 antilipogenic signaling in female adipocytes

Šimunić, Ena; Šešelja, Kate; Podgorski, Iva I.; Belužić, Robert; Popović Hadžija, Marijana; Pinterić Mavar, Marija; Rešetar, Mirta; Halasz, Mirna; Jaganjac, Morana; Bujak, Ivana Tartaro; Protrka, Marta; Balog, Tihomir; Stojanović, Sara; Korać, Aleksandra; Sobočanec, Sandra (2026) Sirt3 deficiency impairs AMPK–Acc1 antilipogenic signaling in female adipocytes. Molecular Biology Reports, 53 (1). ISSN 0301-4851

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Abstract

Background: Biological sex influences adipose tissue function, while impaired adipogenesis contributes to adipose dysfunction. Sirtuin 3 (Sirt3), a mitochondrial NAD+-dependent deacetylase involved in oxidative metabolism and stress adaptation, remains insufficiently defined in adipogenic differentiation. We investigated how Sirt3 and sex shape adipogenic phenotype in mouse embryonic fibroblast (MEF)-derived adipocytes. Methods and Results: Male and female Sirt3 wild-type (WT) and knockout (KO) mouse MEFs were differentiated into adipocyte-like cells and analyzed by Oil Red O staining, confocal microscopy, lipid droplet morphometry, adipogenic gene expression, fatty acid profiling, LC–MS metabolomics, immunoblotting, and transmission electron microscopy (n = 3–5 biological replicates per group). All groups induced adipogenic marker expression and formed lipid rich adipocyte-like cells, with female KO adipocytes showing the strongest lipid storage phenotype. In females, bortezomib (BTZ) increased AMPK and Acc1 phosphorylation in WT adipocytes, whereas KO cells showed reduced basal pAMPK/AMPK and failed to mount a comparable AMPK–Acc1 response. AICAR failed to restore AMPK–Acc1 signaling in KO adipocytes. Sirt3 deficiency increased Scd1 abundance and the C16:1/C16:0 desaturation index. BTZ reduced Scd1 in KO cells without normalizing the elevated desaturation ratio. Metabolomics indicated predominantly BTZ-associated glycerophospholipid and lysophospholipid remodeling. Qualitative ultrastructural analysis revealed BTZ-associated organelle stress, most evident in KO adipocytes. Conclusions: Sirt3 deficiency promotes a female biased lipid storage phenotype linked to impaired AMPK–Acc1 antilipogenic signaling, reduced lipid turnover, and persistent Scd1-associated fatty acid desaturation, supporting a model in which female adipocytes rely on Sirt3-dependent metabolic control during adipogenesis.

Item Type:	Article
Uncontrolled Keywords:	Sirtuin 3; sex differences; adipogenesis; de novo lipogenesis; AMPK-Acc1 signaling; bortezomib
Subjects:	BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences > Human Genetics, Genomics and Proteomics
Divisions:	Division of Materials Chemistry Division of Molecular Medicine
Projects:	Project title Project leader Project code Project type Istraživanje spolno specifičnih metaboličkih učinaka Sirtuina 3 kod bolesti povezanih s pretilošću – Obese Sirt Sandra Sobočanec IP-2022-10-4806 HrZZ
Depositing User:	Sandra Sobočanec
Date Deposited:	11 Nov 2026 10:45
URI:	https://fulir.irb.hr:/id/eprint/12198
DOI:	10.1007/s11033-026-12892-7

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