Lee Hye-Jin, Jin Bo-Yeong, Park Mi-Rae, Kim Nam Hoon, Seo Kwan Sik, Jeong Yong Taek, Wada Tsutomu, Lee Jun-Seok, Choi Sang-Hyun, Kim Dong-Hoon
Department of Pharmacology, Korea University College of Medicine, Seoul 02841, Republic of Korea; BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea.
Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, Republic of Korea.
Life Sci. 2023 Nov 1;332:122101. doi: 10.1016/j.lfs.2023.122101. Epub 2023 Sep 18.
We investigated whether modulation of white adipose tissue (WAT) vasculature regulates rebound weight gain (RWG) after caloric restriction (CR) in mice fed a high-fat diet (HFD).
We compared changes in energy balance, hypothalamic neuropeptide gene expression, and characteristics of WAT by RT-qPCR, ELISA, immunohistochemistry, and adipose-derived stromal vascular fraction spheroid sprouting assay in obese mice fed a HFD ad libitum (HFD-AL), mice under 40 % CR for 3 or 4 weeks, mice fed HFD-AL for 3 days after CR (CRAL), and CRAL mice treated with TNP-470, an angiogenic inhibitor.
WAT angiogenic genes were expressed at low levels, but WAT vascular density was maintained in the CR group compared to that in the HFD-AL group. The CRAL group showed RWG, fat regain, and hyperphagia with higher expression of angiogenic genes and reduced pericyte coverage of the endothelium in WAT on day 3 after CR compared to the CR group, indicating rapidly increased angiogenic activity after CR. Administration of TNP-470 suppressed RWG, fat regain, and hyperphagia only after CR compared to the CRAL group. Changes in circulating leptin levels and hypothalamic neuropeptide gene expression were correlated with changes in weight and fat mass, suggesting that TNP-470 suppressed hyperphagia independently of the hypothalamic melanocortin system. Additionally, TNP-470 increased gene expression related to thermogenesis, fuel utilization, and browning in brown adipose tissue (BAT) and WAT, indicating TNP-470-induced increase in thermogenesis.
Modulation of the WAT vasculature attenuates RWG after CR by suppressing hyperphagia and increasing BAT thermogenesis and WAT browning.
我们研究了在高脂饮食（HFD）喂养的小鼠中，白色脂肪组织（WAT）血管系统的调节是否能调控热量限制（CR）后的体重反弹增加（RWG）。
我们通过实时定量聚合酶链反应（RT-qPCR）、酶联免疫吸附测定（ELISA）、免疫组织化学以及脂肪来源的基质血管成分球状体发芽试验，比较了自由进食HFD的肥胖小鼠（HFD-AL）、40%热量限制3周或4周的小鼠、热量限制后自由进食HFD 3天的小鼠（CRAL）以及用血管生成抑制剂TNP-470处理的CRAL小鼠的能量平衡变化、下丘脑神经肽基因表达和WAT的特征。
与HFD-AL组相比，CR组WAT血管生成基因表达水平较低，但WAT血管密度得以维持。与CR组相比，CRAL组在热量限制后第3天出现体重反弹增加、脂肪恢复和食欲亢进，同时血管生成基因表达增加，WAT中内皮细胞的周细胞覆盖减少，表明热量限制后血管生成活性迅速增加。与CRAL组相比，仅在热量限制后给予TNP-470可抑制体重反弹增加、脂肪恢复和食欲亢进。循环瘦素水平和下丘脑神经肽基因表达的变化与体重和脂肪量的变化相关，这表明TNP-470独立于下丘脑促黑素细胞皮质素系统抑制食欲亢进。此外，TNP-470增加了棕色脂肪组织（BAT）和WAT中与产热、燃料利用和褐变相关的基因表达，表明TNP-470诱导产热增加。
WAT血管系统的调节通过抑制食欲亢进以及增加BAT产热和WAT褐变来减轻热量限制后的体重反弹增加。
