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PPARγ and PPARα synergize to induce robust browning of white fat in vivo.
Molecular Metabolism ( IF 8.1 ) Pub Date : 2020-02-18 , DOI: 10.1016/j.molmet.2020.02.007
Tobias Kroon 1 , Matthew Harms 2 , Stefanie Maurer 2 , Laurianne Bonnet 3 , Ida Alexandersson 1 , Anna Lindblom 2 , Andrea Ahnmark 2 , Daniel Nilsson 3 , Peter Gennemark 2 , Gavin O'Mahony 2 , Victoria Osinski 4 , Coleen McNamara 4 , Jeremie Boucher 1
Affiliation  

Objective

Peroxisome proliferator-activated receptors (PPARs) are key transcription factors that regulate adipose development and function, and the conversion of white into brown-like adipocytes. Here we investigated whether PPARα and PPARγ activation synergize to induce the browning of white fat.

Methods

A selection of PPAR activators was tested for their ability to induce the browning of both mouse and human white adipocytes in vitro, and in vivo in lean and obese mice.

Results

All dual PPARα/γ activators tested robustly increased uncoupling protein 1 (Ucp1) expression in both mouse and human adipocytes in vitro, with tesaglitazar leading to the largest Ucp1 induction. Importantly, dual PPARα/γ activator tesaglitazar strongly induced browning of white fat in vivo in both lean and obese male mice at thermoneutrality, greatly exceeding the increase in Ucp1 observed with the selective PPARγ activator rosiglitazone. While selective PPARγ activation was sufficient for the conversion of white into brown-like adipocytes in vitro, dual PPARα/γ activation was superior to selective PPARγ activation at inducing white fat browning in vivo. Mechanistically, the superiority of dual PPARα/γ activators is mediated at least in part via a PPARα-driven increase in fibroblast growth factor 21 (FGF21). Combined treatment with rosiglitazone and FGF21 resulted in a synergistic increase in Ucp1 mRNA levels both in vitro and in vivo. Tesaglitazar-induced browning was associated with increased energy expenditure, enhanced insulin sensitivity, reduced liver steatosis, and an overall improved metabolic profile compared to rosiglitazone and vehicle control groups.

Conclusions

PPARγ and PPARα synergize to induce robust browning of white fat in vivo, via PPARγ activation in adipose, and PPARα-mediated increase in FGF21.



中文翻译:

PPARγ 和 PPARα 协同作用以诱导体内白色脂肪的强烈褐变。

客观的

过氧化物酶体增殖物激活受体 (PPAR) 是调节脂肪发育和功能以及将白色转化为棕色样脂肪细胞的关键转录因子。在这里,我们研究了 PPARα 和 PPARγ 激活是否协同诱导白色脂肪的褐变。

方法

测试了选择的 PPAR 激活剂在体外以及在瘦和肥胖小鼠体内诱导小鼠和人类白色脂肪细胞褐变的能力。

结果

所有双 PPARα/γ 激活剂都在体外测试了小鼠和人类脂肪细胞中解偶联蛋白 1 ( Ucp1 ) 表达的显着增加,而 tesaglitazar 导致最大的Ucp1诱导。重要的是,双 PPARα/γ 激活剂 tesaglitazar在热中性条件下,在瘦和肥胖雄性小鼠体内强烈诱导白色脂肪褐变,大大超过了使用选择性 PPARγ 激活剂罗格列酮观察到的Ucp1增加。虽然选择性 PPARγ 激活足以在体外将白色转化为棕色样脂肪细胞,但在体内诱导白色脂肪褐变方面,双重 PPARα/γ 激活优于选择性 PPARγ 激活. 从机制上讲,双 PPARα/γ 激活剂的优势至少部分是通过 PPARα 驱动的成纤维细胞生长因子 21 (FGF21) 的增加来介导的。罗格列酮和 FGF21 的联合治疗导致体外体内Ucp1 mRNA 水平的协同增加。与罗格列酮和赋形剂对照组相比,Tesaglitazar 诱导的褐变与能量消耗增加、胰岛素敏感性增强、肝脏脂肪变性减少以及整体代谢状况改善有关。

结论

PPARγ 和 PPARα 协同作用,通过脂肪中的 PPARγ 活化和 PPARα 介导的 FGF21 增加,在体内诱导白色脂肪的强烈褐变。

更新日期:2020-02-18
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