Poon Kinning, Alam Mohammad, Karatayev Olga, Barson Jessica R, Leibowitz Sarah F
Laboratory of Behavioral Neurobiology, The Rockefeller University, New York City, New York, USA.
J Neurochem. 2015 Dec;135(5):918-31. doi: 10.1111/jnc.13298. Epub 2015 Sep 29.
Ingestion of a high-fat diet composed mainly of the saturated fatty acid, palmitic (PA), and the unsaturated fatty acid, oleic (OA), stimulates transcription in the brain of the opioid neuropeptide, enkephalin (ENK), which promotes intake of substances of abuse. To understand possible underlying mechanisms, this study examined the nuclear receptors, peroxisome proliferator-activated receptors (PPARs), and tested in hypothalamic and forebrain neurons from rat embryos whether PPARs regulate endogenous ENK and the fatty acids themselves affect these PPARs and ENK. The first set of experiments demonstrated that knocking down PPARδ, but not PPARα or PPARγ, increased ENK transcription, activation of PPARδ by an agonist decreased ENK levels, and PPARδ neurons coexpressed ENK, suggesting that PPARδ negatively regulates ENK. In the second set of experiments, PA treatment of hypothalamic and forebrain neurons had no effect on PPARδ protein while stimulating ENK mRNA and protein, whereas OA increased both mRNA and protein levels of PPARδ in forebrain neurons while having no effect on ENK mRNA and increasing ENK levels. These findings show that PA has a strong, stimulatory effect on ENK and weak effect on PPARδ protein, whereas OA has a strong stimulatory effect on PPARδ and weak effect on ENK, consistent with the inhibitory effect of PPARδ on ENK. They suggest a function for PPARδ, perhaps protective in nature, in embryonic neurons exposed to fatty acids from a fat-rich diet and provide evidence for a mechanism contributing to differential effects of saturated and monounsaturated fatty acids on neurochemical systems involved in consummatory behavior. Our findings show that PPARδ in forebrain and hypothalamic neurons negatively regulates enkephalin (ENK), a peptide known to promote ingestive behavior. This inverse relationship is consistent with our additional findings, that a saturated (palmitic; PA) compared to a monounsaturated fatty acid (oleic; OA) has a strong stimulatory effect on ENK and weak effect on PPARδ. These results suggest that PPARδ protects against the neuronal effects of fatty acids, which differentially affect neurochemical systems involved in ingestive behavior.
摄入主要由饱和脂肪酸棕榈酸（PA）和不饱和脂肪酸油酸（OA）组成的高脂饮食，会刺激大脑中阿片类神经肽脑啡肽（ENK）的转录，而脑啡肽会促进对成瘾物质的摄取。为了了解可能的潜在机制，本研究检测了核受体过氧化物酶体增殖物激活受体（PPARs），并在大鼠胚胎的下丘脑和前脑神经元中进行测试，以探究PPARs是否调节内源性脑啡肽，以及脂肪酸本身是否影响这些PPARs和脑啡肽。第一组实验表明，敲低PPARδ而非PPARα或PPARγ会增加脑啡肽转录，激动剂激活PPARδ会降低脑啡肽水平，且PPARδ神经元与脑啡肽共表达，这表明PPARδ对脑啡肽起负调节作用。在第二组实验中，用PA处理下丘脑和前脑神经元对PPARδ蛋白无影响，但会刺激脑啡肽mRNA和蛋白表达，而OA会增加前脑神经元中PPARδ的mRNA和蛋白水平，对脑啡肽mRNA无影响，但会增加脑啡肽水平。这些发现表明，PA对脑啡肽有强烈的刺激作用，对PPARδ蛋白作用较弱，而OA对PPARδ有强烈的刺激作用，对脑啡肽作用较弱，这与PPARδ对脑啡肽的抑制作用一致。它们提示了PPARδ在暴露于富含脂肪饮食中的脂肪酸的胚胎神经元中的一种功能，可能具有保护性质，并为饱和脂肪酸和单不饱和脂肪酸对参与消费行为的神经化学系统产生不同影响的机制提供了证据。我们的研究结果表明，前脑和下丘脑神经元中的PPARδ对脑啡肽（ENK）起负调节作用，脑啡肽是一种已知可促进摄食行为的肽。这种反向关系与我们的其他发现一致，即与单不饱和脂肪酸（油酸；OA）相比，饱和脂肪酸（棕榈酸；PA）对脑啡肽有强烈的刺激作用，对PPARδ作用较弱。这些结果表明，PPARδ可保护神经元免受脂肪酸的影响，脂肪酸对参与摄食行为的神经化学系统有不同影响。
