ABCG1 orchestrates adipose tissue macrophage plasticity and insulin resistance in obesity by rewiring saturated fatty acid pools
The mechanisms governing adipose tissue macrophage (ATM) metabolic adaptation during diet-induced obesity (DIO) are poorly understood. In obese adipose tissue, ATMs are exposed to lipid fluxes, which can influence the activation of specific inflammatory and metabolic programs and contribute to the development of obesity-associated insulin resistance and other metabolic disorders. In the present study, we demonstrate that the membrane ATP-binding cassette g1 (Abcg1) transporter controls the ATM functional response to fatty acids (FAs) carried by triglyceride-rich lipoproteins, which are abundant in high-energy diets. Mice genetically lacking Abcg1 in the myeloid lineage presented an ameliorated inflammatory status in adipose tissue and reduced insulin resistance. Abcg1-deficient ATMs exhibited a less inflammatory phenotype accompanied by a low bioenergetic profile and modified FA metabolism. A closer look at the ATM lipidome revealed a shift in the handling of FA pools, including a redirection of saturated FAs from membrane phospholipids to lipid droplets, leading to a reduction in membrane rigidity and neutralization of proinflammatory FAs. ATMs from human individuals with obesity presented the same reciprocal relationship between <i>ABCG1</i> expression and this inflammatory and metabolic status. Abolition of this protective, anti-inflammatory phenotype in Abcg1-deficient ATMs was achieved through restoration of lipoprotein lipase (Lpl) activity, thus delineating the importance of the Abcg1/Lpl axis in controlling ATM metabolic inflammation. Overall, our study identifies the rewiring of FA pools by Abcg1 as a major pathway orchestrating ATM plasticity and insulin resistance in DIO.
Authors
- Wilfried Le Goff (ORCID: https://orcid.org/0000-0002-7611-9644)
- Maryse Guérin (ORCID: https://orcid.org/0000-0003-0150-1360)
- Éric Frisdal
- Pukar KC (ORCID: https://orcid.org/0000-0002-8690-1795)
- Céline Cruciani‐Guglielmacci (ORCID: https://orcid.org/0000-0002-2562-5360)
- Isabelle Guillas (ORCID: https://orcid.org/0000-0002-6073-0529)
- Philippe Lesnik (ORCID: https://orcid.org/0000-0002-6909-7715)
- Nicolas Venteclef (ORCID: https://orcid.org/0000-0002-6313-1214)
- Maharajah Ponnaiah (ORCID: https://orcid.org/0000-0001-7761-4228)
- Jessica Denom (ORCID: https://orcid.org/0000-0002-8507-058X)
- Gordan Lauc (ORCID: https://orcid.org/0000-0003-1840-9560)
- Marie Lhomme (ORCID: https://orcid.org/0000-0002-6335-4506)
- Hervé Durand (ORCID: https://orcid.org/0000-0002-8167-4693)
- Marc Diedisheim (ORCID: https://orcid.org/0000-0002-0418-1107)
- Clément Materne (ORCID: https://orcid.org/0000-0003-2605-2231)
- Anatol Kontush (ORCID: https://orcid.org/0000-0002-9008-7335)
- Florence Deknuydt
- Veronica D. Dahik (ORCID: https://orcid.org/0000-0003-3746-0281)
- Olivier Bluteau (ORCID: https://orcid.org/0000-0002-6943-8858)
- Antoine Soprani
- Ivan Gudelj (ORCID: https://orcid.org/0000-0003-0624-7170)
- Chr̀istophe Magnan (ORCID: https://orcid.org/0000-0002-7044-2571)
- Eric Bun
- Canelle Reydellet (ORCID: https://orcid.org/0009-0002-9445-7206)
- Lise Hardy (ORCID: https://orcid.org/0000-0002-3598-2812)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- Sorbonne Université (FR)
- Institut Necker Enfants Malades (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Pitié-Salpêtrière Hospital (FR)
- Genos (Croatia) (HR)
- Unit of Functional and Adaptive Biology (FR)
- Science Research Laboratory (US)
- Hôpital Charles-Foix (FR)
- Fondation pour l’innovation en Cadiométabolisme et Nutrition (FR)
- Générale de Santé (FR)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2024-12-11
- DOI
- https://doi.org/10.1126/scitranslmed.adi6682
- Citations
- 8
- Primary Topic
- Cholesterol and Lipid Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 4.58