White-to-brite conversion in human adipocytes promotes metabolic reprogramming towards fatty acid anabolic and catabolic pathways.
White-to-brite conversion in human adipocytes promotes metabolic reprogramming towards fatty acid anabolic and catabolic pathways.
复制标题
人脂肪细胞中的白色至勃液转化促进了对脂肪酸合成代谢和分解代谢途径的代谢重编程。
DOI：
10.1016/j.molmet.2016.03.002
复制
发表时间：
2016-05
影响因子：
8.1
通讯作者：
Langin D
中科院分区：
文献类型：
--
作者：
Barquissau V;Beuzelin D;Pisani DF;Beranger GE;Mairal A;Montagner A;Roussel B;Tavernier G;Marques MA;Moro C;Guillou H;Amri EZ;Langin D
具有产热活性的脂肪库已在人类中被发现。在小鼠中，白色脂肪库中出现的产热脂肪细胞（所谓的白中棕，即白色或米色脂肪细胞）可以防止肥胖和胰岛素抵抗。白色脂肪细胞可能来源于白色脂肪细胞的直接转化。这项工作的目的是表征人类脂肪细胞的代谢。将人多能脂肪干细胞分化为白色脂肪细胞，然后在第14天至第18天使用过氧化物酶体增殖物激活受体(PPAR)γ或PPARα激动剂处理。采用DNA微阵列和RT-qPCR检测基因表达谱。从原代培养的分化的人前脂肪细胞中证实了mRNA水平的变化。用放射性示踪剂、Western blot分析和耗氧量评估研究脂肪酸和葡萄糖代谢。利用siRNA实现了丙酮酸脱氢酶激酶4 （PDK4）的敲低。在体内，用β3-肾上腺素能受体激动剂（CL316,243）处理野生型和ppar α-缺失小鼠，诱导白色脂肪库中白色脂肪细胞的出现。测定大鼠腹股沟白色脂肪组织mRNA和蛋白水平。PPAR激动剂促进白色脂肪细胞转化为显示白色分子模式的细胞。这种转化与导致主要代谢适应的转录变化有关。脂肪酸合成代谢，即脂肪酸酯化成甘油三酯，分解代谢，即脂肪分解和脂肪酸氧化，都增加了。葡萄糖的利用从氧化转向甘油-3-磷酸的生产，以合成甘油三酯。这种代谢转变依赖于通过丙酮酸脱氢酶复合物失活而激活PDK4。在体内，野生型小鼠对cl316243的反应显著诱导PDK4表达，而在ppar α-缺失的小鼠中，这种增加被减弱，显示出受损的增生性反应。人类白色脂肪细胞转化为白脂肪细胞导致了一个主要的代谢重编程，诱导脂肪酸合成代谢和分解代谢途径。PDK4将葡萄糖从氧化转向甘油三酯合成，并倾向于使用脂肪酸作为解偶联线粒体的能量来源。PPARγ和α激动剂诱导人白色脂肪细胞转化为白色脂肪细胞。脂肪酸的合成代谢和分解代谢在人脂肪细胞中被激活。葡萄糖在白垩脂肪细胞中的使用由氧化转变为甘油生成。PDK4诱导负责从葡萄糖到脂肪酸氧化的转变。
Fat depots with thermogenic activity have been identified in humans. In mice, the appearance of thermogenic adipocytes within white adipose depots (so-called brown-in-white i.e., brite or beige adipocytes) protects from obesity and insulin resistance. Brite adipocytes may originate from direct conversion of white adipocytes. The purpose of this work was to characterize the metabolism of human brite adipocytes. Human multipotent adipose-derived stem cells were differentiated into white adipocytes and then treated with peroxisome proliferator-activated receptor (PPAR)γ or PPARα agonists between day 14 and day 18. Gene expression profiling was determined using DNA microarrays and RT-qPCR. Variations of mRNA levels were confirmed in differentiated human preadipocytes from primary cultures. Fatty acid and glucose metabolism was investigated using radiolabelled tracers, Western blot analyses and assessment of oxygen consumption. Pyruvate dehydrogenase kinase 4 (PDK4) knockdown was achieved using siRNA. In vivo, wild type and PPARα-null mice were treated with a β3-adrenergic receptor agonist (CL316,243) to induce appearance of brite adipocytes in white fat depot. Determination of mRNA and protein levels was performed on inguinal white adipose tissue. PPAR agonists promote a conversion of white adipocytes into cells displaying a brite molecular pattern. This conversion is associated with transcriptional changes leading to major metabolic adaptations. Fatty acid anabolism i.e., fatty acid esterification into triglycerides, and catabolism i.e., lipolysis and fatty acid oxidation, are increased. Glucose utilization is redirected from oxidation towards glycerol-3-phophate production for triglyceride synthesis. This metabolic shift is dependent on the activation of PDK4 through inactivation of the pyruvate dehydrogenase complex. In vivo, PDK4 expression is markedly induced in wild-type mice in response to CL316,243, while this increase is blunted in PPARα-null mice displaying an impaired britening response. Conversion of human white fat cells into brite adipocytes results in a major metabolic reprogramming inducing fatty acid anabolic and catabolic pathways. PDK4 redirects glucose from oxidation towards triglyceride synthesis and favors the use of fatty acids as energy source for uncoupling mitochondria. PPARγ and α agonists induce conversion of human white into brite adipocytes. Fatty acid anabolism and catabolism are activated in human brite adipocytes. Glucose use in brite adipocytes is redirected from oxidation to glyceroneogenesis. PDK4 induction is responsible for the shift from glucose to fatty acid oxidation.