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<p>Adipocyte dysfunction is a major driver of obesity-associated cardiometabolic disease, underscoring the need to understand how lipid storage and mobilization are regulated and disrupted. The ER-anchored protein Seipin governs lipid droplet (LD) biogenesis and ER-LD and ER–mitochondria (MAM) contacts, and its loss impairs calcium transfer and causes lipodystrophy. Here, we investigated whether Seipin coordinates MAM and ER-LD remodeling during adipocyte lipid handling. In subcutaneous adipose tissue from inducible Seipin-knockout mice, electron microscopy and proximity ligation assays revealed that feeding reduces MAMs while increasing ER-LD and mitochondria-LD contacts, a remodeling abolished by Seipin deficiency. Lipid loading elevated tripartite MAM-LD contacts in controls but not knockouts. Fluorescence recovery after photobleaching showed that impaired triglyceride transfer to LDs in Seipin-deficient cells was rescued by the MAM-LD-stabilizing peptide ‘Linker-ER-Mi’, in a calcium-dependent manner. During adipogenesis and lipid loading, MAM-LD contacts increased, whereas MAM-cytosolic mitochondria contacts declined; however, obesity blunted this remodeling. Furthermore, disrupting membrane contact sites impaired lipid flux, lipolysis, and insulin signaling. Taken together, these findings identify MAM-LD as regulators of adipocyte metabolic flexibility.</p>

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Tripartite ER-mitochondria-lipid droplets contact sites control adipocyte metabolic flexibility

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月22日

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  • Marie Palard,
  • Gilliane Chadeuf,
  • Maxime Carpentier,
  • Clotilde C N Renaud,
  • Samuel Frey,
  • Mikael Croyal,
  • Rola Shaaban,
  • Samy Hadjadj,
  • Chloe Cloteau,
  • Naima El Khallouki,
  • Perrine Bomme,
  • Soazig Le Lay,
  • Manuel Majrouh,
  • Perrine Paul-Gilloteaux,
  • Alexandre Humbert,
  • Christine Durand,
  • Nicolas Bertocchini,
  • Laurence Dubreil,
  • Yoann Combot,
  • Antria Antreou,
  • Cedric Le May,
  • Simon Ducheix,
  • Bertrand Cariou,
  • Francesca Giordano,
  • Jennifer Rieusset,
  • Abdou Rachid Thiam,
  • Xavier Prieur

摘要

Adipocyte dysfunction is a major driver of obesity-associated cardiometabolic disease, underscoring the need to understand how lipid storage and mobilization are regulated and disrupted. The ER-anchored protein Seipin governs lipid droplet (LD) biogenesis and ER-LD and ER–mitochondria (MAM) contacts, and its loss impairs calcium transfer and causes lipodystrophy. Here, we investigated whether Seipin coordinates MAM and ER-LD remodeling during adipocyte lipid handling. In subcutaneous adipose tissue from inducible Seipin-knockout mice, electron microscopy and proximity ligation assays revealed that feeding reduces MAMs while increasing ER-LD and mitochondria-LD contacts, a remodeling abolished by Seipin deficiency. Lipid loading elevated tripartite MAM-LD contacts in controls but not knockouts. Fluorescence recovery after photobleaching showed that impaired triglyceride transfer to LDs in Seipin-deficient cells was rescued by the MAM-LD-stabilizing peptide ‘Linker-ER-Mi’, in a calcium-dependent manner. During adipogenesis and lipid loading, MAM-LD contacts increased, whereas MAM-cytosolic mitochondria contacts declined; however, obesity blunted this remodeling. Furthermore, disrupting membrane contact sites impaired lipid flux, lipolysis, and insulin signaling. Taken together, these findings identify MAM-LD as regulators of adipocyte metabolic flexibility.