Palmitate-induced ER stress and subsequent C 1 HOP activation attenuates leptin and IGF1expression in the brain

Authors: MARWARHA, GURDEEP - University Of North Dakota; Larson, Kate; SCHOMMER, JARED - University Of North Dakota; COLLINS, DAVID - University Of North Dakota; GHRIBI, OTHMAN - University Of North Dakota

Submitted to: Cellular Signaling
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/18/2016
Publication Date: 11/1/2017
Publication URL: https://handle.nal.usda.gov/10113/5832854
Citation: Marwarha, G., Larson, K.J., Schommer, J., Collins, D., Ghribi, O. 2017. Palmitate-induced ER stress and subsequent C 1 HOP activation attenuates leptin and IGF1expression in the brain. Cellular Signaling. 28(11):1789-1805.

Interpretive Summary: In this manuscript, we described how dietary saturated fat such as palmitate can modulate the expression of hormones called insulin like growth hormone-1 (IGF-1) and leptin. These two hormones are known to play a major role in the development of several neurodegenerative diseases. Results presented in this study showed that dietary palmitate fed to mice can increase leptin and IGF-1 levels in the brain. We also showed that the rise in brain leptin and IGF-1 levels parallel that of a stress response in brain cells measured by increased levels of a protein called C/EBP Homologous Protein or CHOP. These results provide new information regarding how dietary saturated fat such as palmitate can contribute to development of neurodegenerative diseases by influencing leptin and IGF-1 levels in the brain and by activating CHOP protein.

Technical Abstract: Background: 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/EBPa, 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. Methods: 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. Results: We demonstrate that palmitate induces ER stress and mitigates 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. 45 Conclusion: 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.