Aupetit Alex, Decaunes Pauline, Belles Chloé, Riant Elodie, Galitzky Jean, Chapouly Candice, Laisné Margaux, Flores-Flores Rémy, Chaput Benoit, Vié Katell, Arnal Jean-François, Bouloumié Anne, Briot Anaïs
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).
Inserm, UMR1297, Team ESTER, I2MC, Institute of Metabolic and Cardiovascular Diseases, Université de Toulouse, France (E.R., J.-F.A.).
Arterioscler Thromb Vasc Biol. 2023 May;43(5):684-696. doi: 10.1161/ATVBAHA.122.318876. Epub 2023 Mar 16.
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.
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.
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.
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.
脂肪库适应燃料供应变化对于代谢灵活性和心脏代谢健康至关重要。负责脂肪库特异性脂质感知和穿梭的机制仍不清楚。脂肪组织微血管内皮细胞（AT-EC）根据进食或禁食状态调节双向脂肪酸通量。AT-EC如何根据AT位置感知并适应代谢变化仍有待确定。
我们将对天然人类AT-EC的转录分析与原代人类AT-EC的体外方法以及在进食和禁食条件下对小鼠的体内和体外研究相结合。
对从臀股部和腹部皮下脂肪组织分离的人类AT-EC进行转录组大规模分析表明，内皮细胞呈现出与脂质处理和Notch信号富集相关的脂肪库特异性特征。我们发现了代谢状态与内皮细胞DLL4（类Delta经典Notch配体4）之间的功能联系，DLL4在禁食时会减少。DLL4通过对巨胞饮作用依赖性长链脂肪酸摄取的非转录调节来调控脂肪酸摄取。重要的是，在致肥胖条件下，DLL4表达响应能量转换状态的变化受损，这一早期改变与全身脂肪酸通量适应缺陷和体重减轻抵抗相吻合。
DLL4是AT-EC调节脂质通量适应性机制中的主要参与者。它可能有助于响应能量转换状态的脂肪库依赖性代谢。肥胖导致的AT-EC改变可能会促进代谢不灵活性和心脏代谢紊乱的发展。
