Pharmacological inhibition of lipolysis prevents adverse metabolic outcomes during glucocorticoid administration.
Pharmacological inhibition of lipolysis prevents adverse metabolic outcomes during glucocorticoid administration.
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DOI：
10.1016/j.molmet.2023.101751
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发表时间：
2023-08
影响因子：
8.1
通讯作者：
Noland, Robert C.
中科院分区：
文献类型：
--
作者：
Linden, Melissa A.;Burke, Susan J.;Pirzadah, Humza A.;Huang, Tai-Yu;Batdorf, Heidi M.;Mohammed, Walid K.;Jones, Katarina A.;Ghosh, Sujoy;Campagna, Shawn R.;Collier, J. Jason;Noland, Robert C.
糖皮质激素是最常用的抗炎药物之一；然而，长期治疗会促进医源性（药物性）糖尿病。作为其生理作用的一部分，糖皮质激素刺激脂肪分解以节省葡萄糖。我们假设在糖皮质激素治疗期间持续刺激脂肪分解在医源性糖尿病的发展中起着致病作用。雄性C57BL/6J小鼠在饮水中给予100 μg/mL皮质酮（Cort） 2周，饲喂正常饲料（TekLad 8640）或添加脂肪甘油三酯脂肪酶抑制剂（Atglistatin - 2 g/kg日粮）以抑制第一步脂肪分解。在此，我们首次报道糖皮质激素的使用促进了骨骼肌中底物过剩和能量过载的独特状态，这主要是由于内源性燃料的大量调动。抑制脂肪分解保护小鼠免受皮质激素诱导的脂肪量增加、过量异位脂质积累、高胰岛素血症和高血糖症的影响。脂解在皮质介导的病理中所起的作用在不同组织中似乎有所不同。在骨骼肌中，cort诱导的脂肪分解促进了葡萄糖衍生碳向戊糖磷酸和己糖胺生物合成途径的转移，但对cort诱导的基因组适应的贡献小于3%。相比之下，据报道，Cort刺激脂肪分解占肝脏基因组变化的35%，但对肝脏代谢物的影响最小。这些数据支持这样一种观点，即在糖皮质激素治疗期间，对骨骼肌和肝脏有不同影响的脂解激活在医源性糖尿病的进展中起因果作用。Cort通过内源性燃料的动员诱导组织水平的底物过载。抑制脂肪分解可预防糖皮质激素诱导的医源性糖尿病。脂解主要影响在Cort治疗期间肌肉代谢物的改变。在Cort治疗期间，肝脏基因组变化的三分之一是由脂肪溶解引起的。
Glucocorticoids are one of the most commonly prescribed classes of anti-inflammatory drugs; however, chronic treatment promotes iatrogenic (drug-induced) diabetes. As part of their physiological role, glucocorticoids stimulate lipolysis to spare glucose. We hypothesized that persistent stimulation of lipolysis during glucocorticoid therapy plays a causative role in the development of iatrogenic diabetes. Male C57BL/6J mice were given 100 μg/mL corticosterone (Cort) in the drinking water for two weeks and were fed either normal chow (TekLad 8640) or the same diet supplemented with an adipose triglyceride lipase inhibitor (Atglistatin - 2 g/kg diet) to inhibit the first step of lipolysis. Herein, we report for the first time that glucocorticoid administration promotes a unique state of substrate excess and energetic overload in skeletal muscle that primarily results from the rampant mobilization of endogenous fuels. Inhibiting lipolysis protected mice from Cort-induced gains in fat mass, excess ectopic lipid accrual, hyperinsulinemia, and hyperglycemia. The role lipolysis plays in Cort-mediated pathology appears to differ between tissues. Within skeletal muscle, Cort-induced lipolysis facilitated diversion of glucose-derived carbons toward the pentose phosphate and hexosamine biosynthesis pathways but contributed to <3% of the Cort-induced genomic adaptations. In contrast, Cort stimulation of lipolysis accounted for ∼35% of the genomic changes in the liver but had minimal impact on hepatic metabolites reported. These data support the idea that activation of lipolysis plays a causal role in the progression toward iatrogenic diabetes during glucocorticoid therapy with differential impact on skeletal muscle and liver. Cort induces tissue-level substrate overload via mobilization of endogenous fuels. Inhibiting lipolysis protects against glucocorticoid-induced iatrogenic diabetes. Lipolysis primarily impacts metabolite alterations in muscle during Cort therapy. Lipolysis accounts for a third of the genomic changes in liver during Cort therapy.
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影响因子：
5.4
作者：
Grygiel-Górniak B
通讯作者：
Grygiel-Górniak B
影响因子：
3.3
作者：
Fuller, Scott E.;Huang, Tai-Yu;Noland, Robert C.
通讯作者：
Noland, Robert C.
DOI：
10.1152/ajpendo.00410.2020
发表时间：
2021-06-01
影响因子：
5.1
作者：
Huang, Tai-Yu;Linden, Melissa A.;Noland, Robert C.
通讯作者：
Noland, Robert C.
影响因子：
7.7
作者：
Greco, AV;Mingrone, G;Ferrannini, E
通讯作者：
Ferrannini, E
影响因子：
15.9
作者：
de Oliveira, Cristiane;Khatua, Biswajit;Singh, Vijay P.
通讯作者：
Singh, Vijay P.