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Gourdel, M.

Publications and source records attributed to Gourdel, M..

2 recordsLinked to original sources
bioRxiv2025

Extracellular vesicles carrying surface-anchored adiponectin prevent obesity-related metabolic complications by enhancing insulin sensitivity

Adiponectin (Adpn) is a potent insulin-sensitizing adipokine with therapeutic promise for type 2 diabetes (T2D) and metabolic dysfunction-associated steatohepatitis (MASH). Its clinical use is limited by challenges in producing stable, bioactive high-molecular weight forms. Adipocyte-derived extracellular vesicles (EVs) naturally carry oligomeric Adpn on their surface, enhancing hormone stability and activity. Here, we engineered EVs displaying membrane-anchored Adpn (EVPP-Adpn) and control EVs lacking Adpn (EVCTL), and evaluated their metabolic effects in high fat diet (HFD)-induced obesity mice. EVPP-Adpn were purified from HEK293T cells stably transfected with a chimeric Adpn fused to a transmembrane domain and a pilot peptide (PP) directing it to EVs; EVCTL were produced from non-transfected cells. HFD-fed male and female mice received intraperitoneal EV injections for six weeks. EVPP-Adpn improved glucose tolerance and insulin sensitivity, promoted adipocyte lipid storage through insulin-regulated lipogenesis and alleviated MASH features (liver steatosis, inflammation and fibrosis). EVPP-Adpn lowered circulating ceramides and reduced FGF21, indicating improved hepatic metabolism, and activated AKT and AMPK pathways in liver and skeletal muscle, consistent with increased adiponectin signaling. These results demonstrate that surface-anchored Adpn EVs restore tissue-specific insulin signaling and improve obesity-related metabolic dysfunctions, highlighting their potential as a novel biotherapeutic strategy for T2D and MASH.

bioengineering↗
bioRxiv2024

Diurnal regulation of Acyl-CoA synthetase 3 (ACSF3) underlies daily mitochondrial lysine-malonylation and hepatic metabolism

Circadian rhythms are fundamental to maintaining health and are implicated in various diseases. In the liver, daily rhythms are coordinated via the interplay between feeding rhythms and the molecular circadian clock, ensuring metabolic homeostasis. Disruption of feeding rhythms can lead to circadian misalignment, contributing to metabolic disorders, yet the underlying molecular mechanisms remain unclear. Recent evidence suggests that post-translational modifications play a key role in regulating circadian functional output. In this framework, mitochondria serve as a convergence point, integrating rhythms in metabolism, feeding rhythms and the circadian clock. In the present study, we used a multi-omics approach to investigate the role of the Acyl-CoA synthetase 3 (ACSF3) in driving lysine-malonylation and in regulating daily hepatic metabolism. We found that ACSF3 expression and its mediated impact on lysine-malonylation are rhythmic and largely governed by feeding rhythms. While hepatic ACSF3 knockdown did not alter diet-induced metabolic abnormalities, our results demonstrate that ACSF3 plays a role in the diurnal regulation of liver glycogen storage, de novo lipogenesis, and triglyceride synthesis.

physiology↗