Endothelial DLL4 Is an Adipose Depot–Specific Fasting Sensor Regulating Fatty Acid Fluxes

Author:

Aupetit Alex1ORCID,Decaunes Pauline1,Belles Chloé1,Riant Elodie2,Galitzky Jean1,Chapouly Candice3ORCID,Laisné Margaux3ORCID,Flores-Flores Rémy4,Chaput Benoit5,Vié Katell6,Arnal Jean-François2ORCID,Bouloumié Anne1,Briot Anaïs1ORCID

Affiliation:

1. Inserm, UMR1297, Team 1, I2MC, Institute of Metabolic and Cardiovascular Diseases, Université de Toulouse, France (A.A., P.D., C.B., J.G., A. Bouloumié., A. Briot).

2. Inserm, UMR1297, Team ESTER, I2MC, Institute of Metabolic and Cardiovascular Diseases, Université de Toulouse, France (E.R., J.-F.A.).

3. Inserm, UMR 1034, Biology of Cardiovascular Diseases, Univ. Bordeaux, Pessac, France (C.C., M.L.).

4. Inserm, UMR1297, I2MC, Institute of Metabolic and Cardiovascular Diseases, Université de Toulouse, France (R.F.-F.).

5. Department of Plastic and Reconstructive Surgery, Toulouse University Hospital, France (B.C.).

6. Laboratoires Clarins, Pontoise, France (K.V.).

Abstract

Background: Adaptation of fat depots to change in fuel availability is critical for metabolic flexibility and cardiometabolic health. The mechanisms responsible for fat depot-specific lipid sensing and shuttling remain elusive. Adipose tissue microvascular endothelial cells (AT-EC) regulates bidirectional fatty acid fluxes depending on fed or fasted state. How AT-EC sense and adapt to metabolic changes according to AT location remains to be established. Methods: We combined transcriptional analysis of native human AT-EC together with in vitro approaches in primary human AT-EC and in vivo and ex vivo studies of mice under fed and fasted conditions. Results: Transcriptional large-scale analysis of human AT-EC isolated from gluteofemoral and abdominal subcutaneous AT revealed that the endothelium exhibits a fat depot–specific signature associated with lipid handling and Notch signaling enrichment. We uncovered a functional link between metabolic status and endothelial DLL4 (delta-like canonical notch ligand 4), which decreases with fasting. DLL4 regulates fatty acid uptake through nontranscriptional modulation of macropinocytosis-dependent long chain fatty acid uptake. Importantly, the changes in DLL4 expression, in response to energy transition state, is impaired under obesogenic conditions, an early alteration coinciding with a defect in systemic fatty acid fluxes adaptation and a resistance to weight loss. Conclusions: DLL4 is a major actor in the adaptive mechanisms of AT-EC to regulate lipid fluxes. It likely contributes to fat depot-dependent metabolism in response to energy transition states. AT-EC alteration with obesity may favor metabolic inflexibility and the development of cardiometabolic disorders.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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