Palmitic and Stearic Acids Inhibit Chaperone-Mediated Autophagy (CMA) in POMC-like Neurons In Vitro

Rodrigo Espinosa,Pablo Galaz-Davison,Mauricio Budini,Valentina Parra,Iván E Alfaro,Fernando Ormeño,Javiera Rios,Liliana Yantén,Alfredo Criollo,César A Ramírez-Sarmiento,Amelina Albornoz,Patricia V Burgos,Karla Gutiérrez,Eugenia Morselli

doi:10.3390/cells11060920

Abstract

The intake of food with high levels of saturated fatty acids (SatFAs) is associated with the development of obesity and insulin resistance. SatFAs, such as palmitic (PA) and stearic (SA) acids, have been shown to accumulate in the hypothalamus, causing several pathological consequences. Autophagy is a lysosomal-degrading pathway that can be divided into macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Previous studies showed that PA impairs macroautophagy function and insulin response in hypothalamic proopiomelanocortin (POMC) neurons. Here, we show in vitro that the exposure of POMC neurons to PA or SA also inhibits CMA, possibly by decreasing the total and lysosomal LAMP2A protein levels. Proteomics of lysosomes from PA- and SA-treated cells showed that the inhibition of CMA could impact vesicle formation and trafficking, mitochondrial components, and insulin response, among others. Finally, we show that CMA activity is important for regulating the insulin response in POMC hypothalamic neurons. These in vitro results demonstrate that CMA is inhibited by PA and SA in POMC-like neurons, giving an overview of the CMA-dependent cellular pathways that could be affected by such inhibition and opening a door for in vivo studies of CMA in the context of the hypothalamus and obesity.

Highlights

It is well known that the consumption of high-fat diets (HFDs) containing high levels of saturated fatty acids (SatFAs) can lead to obesity and related disorders, such as insulin resistance [1,2]
Previous results have shown that palmitic acid inhibits macroautophagy in hypothalamic POMC-like cells [22,23]
Obesity is a worldwide pandemic problem that increases the risk of developing cardiovascular diseases, non-alcoholic fatty liver, and insulin resistance, among others [2,39]

Summary

Introduction

It is well known that the consumption of high-fat diets (HFDs) containing high levels of saturated fatty acids (SatFAs) can lead to obesity and related disorders, such as insulin resistance [1,2]. A population of hypothalamic neurons is in charge of regulating the food intake balance by sensing circulating lipids and glucose, but changes in this process may lead to metabolic disorders and obesity [3]. Autophagy is a lysosomal-dependent degradation pathway involved in the recycling of functional and unfunctional proteins and organelles [7]. Several studies have indicated that autophagy must be finely regulated as an imbalance in its activity, either positively or negatively, has been associated with diseases, such as cancer [8], neurodegeneration [9], and cardiovascular and metabolic disorders [10,11]. CMA degrades proteins but not organelles and does not require the formation of intermediate vesicles (like macroautophagy) [12,13]

Methods

Results

Conclusion