Agarwal Anil K, Tunison Katie, Horton Jay D, Garg Abhimanyu
Section of Nutrition and Metabolic Diseases, Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX 75390, USA.
iScience. 2024 Mar 26;27(4):109517. doi: 10.1016/j.isci.2024.109517. eCollection 2024 Apr 19.
Both humans and mice with congenital generalized lipodystrophy due to AGPAT2 deficiency develop diabetes mellitus, insulin resistance, and hepatic steatosis, which have been attributed to the near total loss of adipose tissue (AT). Here, we show that regulated AT regeneration in doxycycline (dox)-fed Tg;m mice partially ameliorates hepatic steatosis at 12 weeks of age and causes reduced expression of genes involved in hepatic lipogenesis despite partial (∼30-50%) AT regeneration compared to that in wild-type mice. Compared to chow-fed Tg;m mice, those fed dox diet had markedly reduced serum insulin levels, suggesting an improvement in insulin resistance. Interestingly, the fasting plasma glucose levels in dox-fed Tg;m mice were no different than those in chow-fed wild-type mice. Indirect calorimetry revealed normalization in the energy balance of dox-fed Tg;m mice compared to that in chow-fed mice. This study's findings suggest that partial AT regeneration in lipodystrophic mice can ameliorate metabolic derangements.
由于AGPAT2缺乏导致先天性全身性脂肪营养不良的人类和小鼠都会患糖尿病、胰岛素抵抗和肝脂肪变性，这些都归因于脂肪组织（AT）几乎完全丧失。在此，我们表明，在给予强力霉素（dox）的Tg;m小鼠中，受调控的AT再生在12周龄时部分改善了肝脂肪变性，尽管与野生型小鼠相比AT再生仅部分（约30 - 50%），但仍导致参与肝脏脂肪生成的基因表达降低。与喂食普通饲料的Tg;m小鼠相比，喂食dox饲料的小鼠血清胰岛素水平显著降低，表明胰岛素抵抗有所改善。有趣的是，喂食dox的Tg;m小鼠的空腹血糖水平与喂食普通饲料的野生型小鼠无异。间接测热法显示，与喂食普通饲料的小鼠相比，喂食dox的Tg;m小鼠的能量平衡恢复正常。这项研究的结果表明，脂肪营养不良小鼠的部分AT再生可以改善代谢紊乱。
