Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK.
Genome Med. 2009 Dec 7;1(12):115. doi: 10.1186/gm115.
The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear receptor superfamily. The PPAR family consists of three members: PPARalpha, PPARgamma, and PPARdelta. PPARdelta controls the transcription of genes involved in multiple physiological pathways, including cellular differentiation, lipid metabolism and energy homeostasis. The receptor is expressed almost ubiquitously, with high expression in liver and skeletal muscle. Although the physiological ligands of PPARdelta remain undefined, a number of high affinity synthetic ligands have been developed for the receptor as a therapeutic target for type 2 diabetes mellitus, dyslipidemia and the metabolic syndrome.
In this study, the metabolic role of PPARdelta activation has been investigated in liver, skeletal muscle, blood serum and white adipose tissue from ob/ob mice using a high affinity synthetic ligand and contrasted with PPARgamma activation. To maximize the analytical coverage of the metabolome, (1)H-nuclear magnetic resonance ((1)H-NMR) spectroscopy, gas chromatography-mass spectrometry (GC-MS) and ultra performance liquid chromatography-mass spectrometry (UPLC-MS) were used to examine metabolites from tissue extracts.
Analysis by multivariate statistics demonstrated that PPARdelta activation profoundly affected glycolysis, gluconeogenesis, the TCA cycle and linoleic acid and alpha-linolenic acid essential fatty acid pathways.
Although activation of both PPARdelta and PPARgamma lead to increased insulin sensitivity and glucose tolerance, PPARdelta activation was functionally distinct from PPARgamma activation, and was characterized by increased hepatic and peripheral fatty acid oxidative metabolism, demonstrating the distinctive catabolic role of this receptor compared with PPARgamma.
过氧化物酶体增殖物激活受体（PPARs）是配体激活的转录因子，是核受体超家族的成员。PPAR 家族由三个成员组成：PPARα、PPARγ 和 PPARδ。PPARδ 控制着参与多种生理途径的基因转录，包括细胞分化、脂质代谢和能量稳态。该受体几乎在所有组织中广泛表达，在肝脏和骨骼肌中表达水平较高。尽管 PPARδ 的生理配体仍未确定，但已经开发了许多高亲和力的合成配体作为 2 型糖尿病、血脂异常和代谢综合征的治疗靶点。
本研究使用高亲和力的合成配体研究了过氧化物酶体增殖物激活受体 δ 在 ob/ob 小鼠肝脏、骨骼肌、血清和白色脂肪组织中的代谢作用，并与过氧化物酶体增殖物激活受体 γ 的作用进行了对比。为了最大限度地覆盖代谢组的分析范围，使用了（1）H 核磁共振（1H-NMR）光谱、气相色谱-质谱（GC-MS）和超高效液相色谱-质谱（UPLC-MS）来检测组织提取物中的代谢物。
多变量统计分析表明，过氧化物酶体增殖物激活受体 δ 的激活显著影响了糖酵解、糖异生、三羧酸循环以及亚油酸和α-亚麻酸必需脂肪酸途径。
尽管激活过氧化物酶体增殖物激活受体 δ 和过氧化物酶体增殖物激活受体 γ 都能提高胰岛素敏感性和葡萄糖耐量，但过氧化物酶体增殖物激活受体 δ 的激活在功能上与过氧化物酶体增殖物激活受体 γ 的激活不同，其特征是肝内和外周脂肪酸氧化代谢增加，表明该受体与过氧化物酶体增殖物激活受体 γ 相比具有独特的分解代谢作用。
