title: Differential effects of omega-3 fatty acid docosahexaenoic acid and palmitate on the circadian transcriptional profile of clock genes in immortalized hypothalamic neurons.
abstract: Diets high in saturated fatty acids (SFAs) are associated with the development of circadian dysregulation, obesity, and Type 2 diabetes mellitus. Conversely, polyunsaturated fatty acids (PUFAs) have recently been identified to improve insulin sensitivity, reduce weight gain, and relieve obesity-induced inflammation. While saturated fatty acids, such as the prevalent dietary fatty acid palmitate, have been implicated in circadian disruption, there is a paucity of studies regarding the effects of PUFAs on circadian parameters. Therefore, the immortalized murine neuronal model, mHypoE-37, was utilized to examine the effects of the SFA palmitate and omega-3 PUFA docosahexaenoic acid (DHA) on circadian rhythms. The mHypoE-37 neurons express the core clock genes, Bmal1, Per2, and Rev-erbα, in a circadian manner. 25 μM of palmitate significantly increased the transcriptional expression of Bmal1, without altering the expression of inflammatory markers TLR4, IκBα, and IL-6, nor the orexigenic neuropeptide AgRP, suggesting that the observed disruption of the molecular clock is the result of a mechanism distinct from that of hypothalamic cellular inflammation. Furthermore, treatment with the PUFA DHA resulted in alterations in the circadian expression profile of Bmal1, although differentially from the effects of palmitate. In the presence of DHA, the disruptive effects of palmitate on Bmal1 were less pronounced, suggesting a protective effect of DHA. These studies are the first to identify the potential for omega-3 PUFAs to protect against palmitate-mediated dysregulation of circadian parameters and will ultimately improve the understanding of circadian control mechanisms.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada;
authors.forename: James A
authors.initials: JA
authors.lastname: Greco
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Johanneke E
authors.initials: JE
authors.lastname: Oosterman
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Department of Obstetrics and Gynaecology and Medicine, University of Toronto and Division of Cellular and Molecular Biology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; and d.belsham@utoronto.ca.
authors.forename: Denise D
authors.initials: DD
authors.lastname: Belsham
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000187:drug effects* / Q000235:genetics; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism; D010168:Palmitates / Q000494:pharmacology*; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D059467:Transcriptome / Q000187:drug effects* / Q000235:genetics
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D010168:Palmitates; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D004281:Docosahexaenoic Acids; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases
keywords: cell biology; circadian rhythms; gene expression; hypothalamus; saturated fatty acid; unsaturated fatty acid