Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Int J Obes (Lond). 2018 Mar;42(3):542-551. doi: 10.1038/ijo.2017.222. Epub 2017 Sep 12.
BACKGROUND/OBJECTIVES: We investigated the effect of long-term treatment with lobeglitazone, a novel thiazolidinedione-based activator of peroxisome proliferator-activated receptor gamma, on adipose tissue (AT), focusing on its effects on insulin resistance in obese db/db mice.
Seven-week-old male db/db mice were assigned to either a vehicle-treated (n=8) or lobeglitazone-treated (n=8) group. Lobeglitazone (1 mg kg daily) was injected intraperitoneally for 20 weeks.
Lobeglitazone treatment for 20 weeks resulted in a remarkably improved glycemic index, including significantly decreased glucose levels, enhanced insulin sensitivity and preserved pancreatic beta cells. Both whole body and subcutaneous AT weight increased in the lobeglitazone-treated group. However, lobeglitazone induced an increase in the number of small adipocyte in both epididymal and subcutaneous AT, with a significant weight decrease in the epididymal AT of db/db mice. Using flow cytometry, the CD11c-positive M1 macrophages and CD206-positive M2 macrophages in the epididymal AT were observed to exhibit a decreased M1-to-M2 ratio in lobeglitazone-treated db/db mice. Furthermore, in the lobeglitazone-treated group, interscapular brown AT was clearly visualized by F-fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography (F-FDG-PET/CT) and its mass was significantly greater than that of the vehicle-treated group. In the lobeglitazone-treated group, beige-specific gene expression and the number of mitochondria in white AT were upregulated. Lobeglitazone, with upregulating interferon regulatory factor-4 (a key transcriptional regulator of thermogenesis), promoted the development of brown adipocytes and the differentiation of white adipocytes into beige adipocytes.
Long-term lobeglitazone treatment has a beneficial role in remodeling and ameliorating inflammation in white AT and in glycemic control, in relation to insulin sensitivity in obese db/db mice. Moreover, lobeglitazone induced the differentiation of brown and beige adipocytes. Collectively, our data suggest that lobeglitazone treatment provides promising effects on white and brown AT as well as great improvement in glycemic control, as a potent insulin sensitizer.
背景/目的：我们研究了新型噻唑烷二酮类过氧化物酶体增殖物激活受体γ激动剂罗格列酮（lobeglitazone）的长期治疗对脂肪组织（adipose tissue，AT）的影响，重点关注其对肥胖 db/db 小鼠胰岛素抵抗的作用。
将 7 周龄雄性 db/db 小鼠分为 vehicle 处理组（n=8）和 lobeglitazone 处理组（n=8）。lobeglitazone（1mg/kg 每天）经腹腔内注射 20 周。
经过 20 周的 lobeglitazone 治疗，血糖指数得到显著改善，包括血糖水平显著降低、胰岛素敏感性增强和胰岛β细胞功能得到保护。lobeglitazone 处理组的全身和皮下 AT 重量均增加。然而，lobeglitazone 诱导 db/db 小鼠附睾 AT 中小脂肪细胞数量增加，附睾 AT 重量显著减轻。使用流式细胞术观察到，db/db 小鼠附睾 AT 中的 CD11c 阳性 M1 巨噬细胞和 CD206 阳性 M2 巨噬细胞的 M1 向 M2 比值降低。此外，在 lobeglitazone 处理组中，用 F-氟-2-脱氧-D-葡萄糖正电子发射断层扫描与计算机断层扫描（F-FDG-PET/CT）清楚地观察到肩胛间棕色 AT，并发现其质量明显大于 vehicle 处理组。在 lobeglitazone 处理组中，白色 AT 中的 beige 特异性基因表达和线粒体数量增加。lobeglitazone 通过上调干扰素调节因子-4（产热的关键转录调节因子），促进棕色脂肪细胞的发育和白色脂肪细胞向 beige 脂肪细胞的分化。
长期 lobeglitazone 治疗对肥胖 db/db 小鼠的白色 AT 重塑和炎症改善以及血糖控制（与胰岛素敏感性有关）具有有益作用。此外，lobeglitazone 诱导棕色和 beige 脂肪细胞的分化。总之，我们的数据表明，lobeglitazone 治疗对白色和棕色 AT 具有潜在的治疗效果，并显著改善血糖控制，作为一种有效的胰岛素增敏剂。
