title: Palmitate-induced Endoplasmic Reticulum stress and subsequent C/EBPα Homologous Protein activation attenuates leptin and Insulin-like growth factor 1 expression in the brain.
abstract: The peptide hormones Insulin-like growth factor-1 (IGF1) and leptin mediate a myriad of biological effects - both in the peripheral and central nervous systems. The transcription of these two hormones is regulated by the transcription factor C/EBPα, which in turn is negatively regulated by the transcription factor C/EBP Homologous Protein (CHOP), a specific marker of endoplasmic reticulum (ER) stress. In the peripheral system, disturbances in leptin and IGF-1 levels are implicated in a variety of metabolic diseases including obesity, diabetes, atherosclerosis and cardiovascular diseases. Current research suggests a positive correlation between consumption of diets rich in saturated free fatty acids (sFFA) and metabolic diseases. Induction of ER stress and subsequent dysregulation in the expression levels of leptin and IGF-1 have been shown to mediate sFFA-induced metabolic diseases in the peripheral system. Palmitic acid (palmitate), the most commonly consumed sFFA, has been shown to be up-taken by the brain, where it may promote neurodegeneration. However, the extent to which palmitate induces ER stress in the brain and attenuates leptin and IGF1 expression has not been determined. We fed C57BL/6J mice a palmitate-enriched diet and determined effects on the expression levels of leptin and IGF1 in the hippocampus and cortex. We further determined the extent to which ER stress and subsequent CHOP activation mediate the palmitate effects on the transcription of leptin and IGF1. We demonstrate that palmitate induces ER stress and decreases leptin and IGF1 expression by inducing the expression of CHOP. The molecular chaperone 4-phenylbutyric acid (4-PBA), an inhibitor of ER stress, precludes the palmitate-evoked down-regulation of leptin and IGF1 expression. Furthermore, the activation of CHOP in response to ER stress is pivotal in the attenuation of leptin and IGF1 expression as knocking-down CHOP in mice or in SH-SY5Y and Neuro-2a (N2a) cells rescues the palmitate-induced mitigation in leptin and IGF1 expression. Our study implicates for the first time ER stress-induced CHOP activation in the brain as a mechanistic link in the palmitate-induced negative regulation of leptin and IGF1, two neurotrophic cytokines that play an indispensable role in the mammalian brain.
authors.affiliation: Department of Biomedical Sciences, School of Medicine & Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA.
authors.forename: Gurdeep
authors.initials: G
authors.lastname: Marwarha
authors.affiliation: U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58203, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Claycombe
authors.affiliation: Department of Biomedical Sciences, School of Medicine & Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Schommer
authors.affiliation: Department of Biomedical Sciences, School of Medicine & Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA.
authors.forename: David
authors.initials: D
authors.lastname: Collins
authors.affiliation: Department of Biomedical Sciences, School of Medicine & Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA. Electronic address: othman.ghribi@med.und.edu.
authors.forename: Othman
authors.initials: O
authors.lastname: Ghribi
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010168:Palmitates / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D055503:Protein Multimerization; D051742:Transcription Factor CHOP / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D020738:Leptin; D010168:Palmitates; D051742:Transcription Factor CHOP; D007334:Insulin-Like Growth Factor I
keywords: C/EBP Homologous Protein; CCAAT Enhancer Binding Protein alpha; Endoplasmic Reticulum stress; Insulin-like growth factor 1; Leptin; Palmitic acid