Kroon Tobias, Harms Matthew, Maurer Stefanie, Bonnet Laurianne, Alexandersson Ida, Lindblom Anna, Ahnmark Andrea, Nilsson Daniel, Gennemark Peter, O'Mahony Gavin, Osinski Victoria, McNamara Coleen, Boucher Jeremie
Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; The Lundberg Laboratory for Diabetes Research, University of Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden.
Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Mol Metab. 2020 Jun;36:100964. doi: 10.1016/j.molmet.2020.02.007. Epub 2020 Feb 18.
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.
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.
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.
PPARγ and PPARα synergize to induce robust browning of white fat in vivo, via PPARγ activation in adipose, and PPARα-mediated increase in FGF21.
过氧化物酶体增殖物激活受体（PPARs）是调节脂肪发育和功能以及白色脂肪细胞向棕色样脂肪细胞转化的关键转录因子。在此，我们研究了PPARα和PPARγ激活是否协同诱导白色脂肪褐变。
测试了一系列PPAR激活剂在体外诱导小鼠和人白色脂肪细胞褐变的能力，以及在瘦小鼠和肥胖小鼠体内的诱导能力。
所有测试的双PPARα/γ激活剂在体外均能显著增加小鼠和人脂肪细胞中解偶联蛋白1（Ucp1）的表达，其中替格列扎诱导的Ucp1增加幅度最大。重要的是，双PPARα/γ激活剂替格列扎在热中性条件下能强烈诱导瘦小鼠和肥胖雄性小鼠体内白色脂肪褐变，大大超过选择性PPARγ激活剂罗格列酮所观察到的Ucp1增加。虽然选择性PPARγ激活足以在体外将白色脂肪细胞转化为棕色样脂肪细胞，但双PPARα/γ激活在体内诱导白色脂肪褐变方面优于选择性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）增加来介导的。罗格列酮和FGF21联合治疗在体外和体内均导致Ucp1 mRNA水平协同增加。与罗格列酮和载体对照组相比，替格列扎诱导的褐变与能量消耗增加、胰岛素敏感性增强、肝脏脂肪变性减轻以及整体代谢状况改善有关。
PPARγ和PPARα协同作用，通过脂肪组织中PPARγ的激活以及PPARα介导的FGF21增加，在体内诱导白色脂肪强烈褐变。
