Department of Biochemistry University of Cambridge, Cambridge CB2 1QW, UK.
Genome Biol. 2011 Aug 11;12(8):R75. doi: 10.1186/gb-2011-12-8-r75.
The nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and peroxisome proliferator-activated receptor δ (PPARδ) play central roles in regulating metabolism in adipose tissue, as well as being targets for the treatment of insulin resistance. While the role of PPARγ in regulating insulin sensitivity has been well defined, research into PPARδ has been limited until recently due to a scarcity of selective PPARδ agonists.
The metabolic effects of PPARγ and PPARδ activation have been examined in vivo in white adipose tissue from ob/ob mice and in vitro in cultured 3T3-L1 adipocytes using (1)H nuclear magnetic resonance spectroscopy and mass spectrometry metabolomics to understand the receptors' contrasting roles. These steady state measurements were supplemented with (13)C-stable isotope substrate labeling to assess fluxes, in addition to respirometry and transcriptomic microarray analysis. The metabolic effects of the receptors were readily distinguished, with PPARγ activation characterized by increased fat storage, synthesis and elongation, while PPARδ activation caused increased fatty acid β-oxidation, tricarboxylic acid cycle rate and oxidation of extracellular branch chain amino acids. Stimulated glycolysis and increased fatty acid desaturation were common pathways for the agonists.
PPARγ and PPARδ restore insulin sensitivity through varying mechanisms. PPARδ activation increases total oxidative metabolism in white adipose tissue, a tissue not traditionally thought of as oxidative. However, the increased metabolism of branch chain amino acids may provide a mechanism for muscle atrophy, which has been linked to activation of this nuclear receptor. PPARδ has a role as an anti-obesity target and as an anti-diabetic, and hence may target both the cause and consequences of dyslipidemia.
过氧化物酶体增殖物激活受体 γ（PPARγ）和过氧化物酶体增殖物激活受体 δ（PPARδ）在调节脂肪组织代谢中发挥核心作用，也是治疗胰岛素抵抗的靶点。虽然 PPARγ 在调节胰岛素敏感性方面的作用已得到充分证实，但由于缺乏选择性 PPARδ 激动剂，对 PPARδ 的研究直到最近才受到限制。
利用（1）H 核磁共振波谱和质谱代谢组学技术，在 ob/ob 小鼠的白色脂肪组织中进行体内研究，并在培养的 3T3-L1 脂肪细胞中进行体外研究，检测了 PPARγ 和 PPARδ 激活的代谢效应，以了解两种受体的作用。这些稳态测量结果通过（13）C-稳定同位素底物标记进行了补充，以评估通量，此外还进行了呼吸测定和转录组微阵列分析。两种受体的代谢效应很容易区分，PPARγ 激活的特征是脂肪储存、合成和延长增加，而 PPARδ 激活导致脂肪酸 β-氧化、三羧酸循环速率和细胞外支链氨基酸氧化增加。激动剂的共同途径是刺激糖酵解和增加脂肪酸去饱和。
PPARγ 和 PPARδ 通过不同的机制恢复胰岛素敏感性。PPARδ 激活增加了白色脂肪组织的总氧化代谢，而白色脂肪组织通常不被认为是氧化的。然而，支链氨基酸的代谢增加可能为肌肉萎缩提供了一种机制，肌肉萎缩与这种核受体的激活有关。PPARδ 是一种抗肥胖和抗糖尿病的靶点，因此可能同时针对血脂异常的原因和后果。
