Acute effects of fatty acids on autophagy in NPY neurones

Abstract

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.

The regulation, function, and role of lipophagy, a form of selective autophagy, in metabolic disorders

“…The protective effects of DGAT1 in mice with cardiomyopathy [ 114 – 116 ] suggest that it is more advantageous to store fatty acids in LDs in the form of triglycerides and gradually release these fatty acids through lipolysis or lipophagy than to convert these fatty acids into toxic lipids. In addition, various fatty acids can modulate the rate of autophagic activity [ 117 ], but whether this involves lipophagy remains to be confirmed. As a key function of autophagy, continuous cell quality control ensures that damaged organelles [ 118 ], lipids, and proteins can regulate turnover.…”

Palmitate reduces starvation-induced ER stress by inhibiting ER-phagy in hypothalamic cells

“…However, the role of FFAs in the hypothalamus during fasting, beyond regulation of neuropeptide expression, has not been well elucidated. Given the starvationinduced ER stress [32] and autophagy [31,[33][34][35] in hypothalamic cells, circulating palmitate under fasting might regulate ER stress and ER-phagy, affecting hypothalamic functions.…”

Role of hypothalamic de novo ceramides synthesis in obesity and associated metabolic disorders

“…In NPY/AgRP hypothalamic neurons, autophagy-regulated lipid metabolism has been shown to modulate neuropeptide levels which have immediate effects on food intake [ 63 ]. Interestingly, Milanski and colleagues recently showed that palmitate-mediated induction of autophagy in the NPY-expressing neuronal cell model mHypoE-46 is dependent on de novo ceramide biosynthesis [ 64 ]. These results suggest that increased de novo ceramide biosynthesis in different neuronal populations is involved in the regulation of energy homeostasis.…”