Palmitic Acid Reduces the Autophagic Flux and Insulin Sensitivity Through the Activation of the Free Fatty Acid Receptor 1 (FFAR1) in the Hypothalamic Neuronal Cell Line N43/5

Hernández-Cáceres, María Paz; Toledo-Valenzuela, Lilian; Díaz-Castro, Francisco; Ávalos, Yenniffer; Burgos, Paulina; Narro, Carla; Peña‐Oyarzún, Daniel; Espinoza-Caicedo, Jasson; Cifuentes-Araneda, Flavia; Navarro-Aguad, Fernanda; Riquelme, Cecilia; Troncoso, Rodrigo; Criollo, Alfredo; Morselli, Eugenia

doi:10.3389/fendo.2019.00176

Cited by 46 publications

(53 citation statements)

References 53 publications

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“…LC3-II accumulation caused by hydroxychloroquine was reduced after PA treatment, which confirms the blockade of autophagy in astrocytes [102]. A reduction in autophagic activity has also been described in hypothalamic neurons exposed to PA [103]. On the contrary, autophagy induction by PA has also been reported in cultured astrocytes [91].…”

Section: Involvement Of Astrocyte Autophagy In Systemic Metabolismsupporting

confidence: 67%

The Contribution of Astrocyte Autophagy to Systemic Metabolism

Ortiz-Rodriguez

Arévalo

2020

IJMS

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Autophagy is an essential mechanism to maintain cellular homeostasis. Besides its role in controlling the quality of cytoplasmic components, it participates in nutrient obtaining and lipid mobilization under stressful conditions. Furthermore, autophagy is involved in the regulation of systemic metabolism as its blockade in hypothalamic neurons can affect the central regulation of metabolism and impact body energy balance. Moreover, hypothalamic autophagy can be altered during obesity, one of the main alterations of metabolism nowadays. In this review, we focus on the role of astrocytes, essential cells for brain homeostasis, which represent key metabolic regulators. Astrocytes can sense metabolic signals in the hypothalamus and modulate systemic functions as glucose homeostasis and feeding response. Moreover, the response of astrocytes to obesity has been widely studied. Astrocytes are important mediators of brain inflammation and can be affected by increased levels of saturated fatty acids associated with obesity. Although autophagy plays important roles for astrocyte homeostasis and functioning, the contribution of astrocyte autophagy to systemic metabolism has not been analyzed yet. Furthermore, how obesity can impact astrocyte autophagy is poorly understood. More studies are needed in order to understand the contribution of astrocyte autophagy to metabolism.

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Section: Involvement Of Astrocyte Autophagy In Systemic Metabolismsupporting

confidence: 67%

The Contribution of Astrocyte Autophagy to Systemic Metabolism

Ortiz-Rodriguez

Arévalo

2020

IJMS

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“…28 On the other hand, in mHypoE-43/5 cells, a hypothalamic POMC-expressing neuronal cell line, PA treatment inhibited the autophagic flux associated with reduced insulin sensitivity. 29 Thus, emerging evidence corroborates our current hypothesis that an alteration in autophagic function may play a role in the pathophysiology of human disorders that result from excessive cellular lipid accumulation. For example, short and chronic HFD exposure are able to change levels of autophagy in liver tissue that was linked to steatosis.…”

Section: Introductionsupporting

confidence: 77%

Acute effects of fatty acids on autophagy in NPY neurones

Reginato

Siqueira

Miyamoto

et al. 2020

J Neuroendocrinology

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High-fat diet (HFD) feeding is deleterious to hypothalamic tissue, leading to inflammation and lipotoxicity, as well as contributing to central insulin resistance. Autophagy is a process that restores cellular homeostasis by degrading malfunctioning organelles and proteins. Chronic HFD-feeding down-regulates hypothalamic autophagy. However, the effects of short-term HFD-feeding and the saturated fatty acid palmitate (PA) on hypothalamic autophagy and in neurones that express neuropeptide Y (NPY) and agouti-related peptide remains unknown. Therefore, we assessed hypothalamic autophagy after 1 and 3 days of HFD-feeding. We also injected PA i.c.v and analysed the modulation of autophagy in hypothalamic tissue. Both interventions resulted in changes in autophagy-related gene profiles without significant differences in protein content of p62 and LC3B-II, markers of the autophagy pathway. When we assessed native NPY neurones in brain slices from PA-treated animals, we observed increased levels of Atg7 and LC3B protein in response to PA treatment, indicating the induction of autophagy. We then tested the direct effects of fatty acids using the immortalised hypothalamic NPY-expressing neuronal cell model mHypoE-46. We found that PA, but not palmitoleate (PO) (a monounsaturated fatty acid), was able to induce autophagy. Co-treatment with PA and PO was able to block the PA-mediated induction of autophagy, as assessed by flow cytometry. When the de novo ceramide synthesis pathway was blocked with myriocin pre-treatment, we observed a decrease in PA-mediated induction of autophagy, although there was no change with the toll-like receptor 4 inhibitor, TAK-242. Taken together, these findings provide evidence that saturated and unsaturated fatty acids can differentially regulate hypothalamic autophagy and that ceramide synthesis may be an important mediator of those effects. Understanding the mechanisms by which dietary fats affect autophagy in neurones involved in the control of energy homeostasis will provide potential new pathways for targeting and containing the obesity epidemic.

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“…LC3-II accumulation caused by hydroxychloroquine was reduced after PA treatment, which confirms the blockade of autophagy in astrocytes [113]. A reduction in autophagic activity has been also described in hypothalamic neurons exposed to PA [114]. On the contrary, autophagy induction by PA has been also reported in cultured astrocytes [102].…”

Section: Involvement Of Astrocyte Autophagy In Systemic Metabolismsupporting

confidence: 66%

Autophagy in Astrocytes: Importance for Metabolism

Ortiz-Rodriguez¹,

Arévalo²

2020

Preprint

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Autophagy is an essential mechanism to maintain cellular homeostasis. Besides its role in controlling the quality of cytoplasmic components, it participates in nutrient obtaining and lipid mobilization under stressful conditions. Furthermore, autophagy is involved in the regulation of systemic metabolic, a function mainly performed by neuronal populations of the arcuate nucleus of the hypothalamus. Several studies have shown that blockade of autophagy in these neurons can affect central regulation of metabolism and impact body energy balance. Moreover, hypothalamic autophagy can be altered during obesity. However, neurons are not the only cell type involved in the central regulation of metabolism. Astrocytes, essential cells for brain homeostasis, are key metabolic regulators. They can sense metabolic signals in the hypothalamus and modulate systemic functions as glucose homeostasis and feeding response. Moreover, the response of astrocytes to obesity has been widely studied. Astrocytes are important mediators of brain inflammation and can be affected by increased levels of saturated fatty acids associated to obesity. Although autophagy plays important roles for astrocyte homeostasis and functioning, the contribution of astrocyte autophagy to systemic metabolism has not been analysed. Furthermore, how obesity can impact astrocyte autophagy is poorly understood. More studies are needed in other to understand the contribution of astrocyte autophagy to metabolism.

show abstract

Palmitic Acid Reduces the Autophagic Flux and Insulin Sensitivity Through the Activation of the Free Fatty Acid Receptor 1 (FFAR1) in the Hypothalamic Neuronal Cell Line N43/5

Cited by 46 publications

References 53 publications

The Contribution of Astrocyte Autophagy to Systemic Metabolism

The Contribution of Astrocyte Autophagy to Systemic Metabolism

Acute effects of fatty acids on autophagy in NPY neurones

Autophagy in Astrocytes: Importance for Metabolism

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