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Regulation of the orexigenic neuropeptide, enkephalin, by PPAR δ and fatty acids in neurons of the hypothalamus and forebrain
Author(s) -
Poon Kinning,
Alam Mohammad,
Karatayev Olga,
Barson Jessica R.,
Leibowitz Sarah F.
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13298
Subject(s) - medicine , endocrinology , neuropeptide , peroxisome proliferator activated receptor , enkephalin , orexigenic , forebrain , receptor , biology , hypothalamus , chemistry , neuropeptide y receptor , central nervous system , opioid
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 ( PPAR s), and tested in hypothalamic and forebrain neurons from rat embryos whether PPAR s regulate endogenous ENK and the fatty acids themselves affect these PPAR s and ENK . The first set of experiments demonstrated that knocking down PPAR δ, but not PPAR α or PPAR γ, increased ENK transcription, activation of PPAR δ by an agonist decreased ENK levels, and PPAR δ neurons coexpressed ENK , suggesting that PPAR δ negatively regulates ENK . In the second set of experiments, PA treatment of hypothalamic and forebrain neurons had no effect on PPAR δ protein while stimulating ENK mRNA and protein, whereas OA increased both mRNA and protein levels of PPAR δ 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 PPAR δ protein, whereas OA has a strong stimulatory effect on PPAR δ and weak effect on ENK , consistent with the inhibitory effect of PPAR δ on ENK . They suggest a function for PPAR δ, 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.