Saturated Fatty Acids Modulate Autophagy’s Proteins in the Hypothalamus

Abstract

Autophagy is an important process that regulates cellular homeostasis by degrading dysfunctional proteins, organelles and lipids. In this study, the hypothesis that obesity could lead to impairment in hypothalamic autophagy in mice was evaluated by examining the hypothalamic distribution and content of autophagic proteins in animal with obesity induced by 8 or 16 weeks high fat diet to induce obesity and in response to intracerebroventricular injections of palmitic acid. The results showed that chronic exposure to a high fat diet leads to an increased expression of inflammatory markers and downregulation of autophagic proteins. In obese mice, autophagic induction leads to the downregulation of proteins, such as JNK and Bax, which are involved in the stress pathways. In neuron cell- line, palmitate has a direct effect on autophagy even without inflammatory activity. Understanding the cellular and molecular bases of overnutrition is essential for identifying new diagnostic and therapeutic targets for obesity.

Diabetic phenotype in mouse and humans with β-amyloid pathology reduces the number of microglia around β-amyloid plaques

“…Given the decreased activation of Akt-kinase due to TWD, this was an unexpected finding since the activated Akt-kinase is known to activate mTORC1, which again inhibits the induction of autophagy [102]. However, our observation related to the increased p62 levels is consistent with previous studies reporting increased p62 levels in the peripheral tissues, hypothalamus, and hippocampus of mice on HFD [13,75,104]. Furthermore, HFD has been linked to impaired lysosomal activity [104].…”

Resolvin RvD2 reduces hypothalamic inflammation and rescues mice from diet-induced obesity

“…The anomalous activity of such neurons is characterised, at least in part, by their reduced responsiveness to the adipostatic hormones, leptin and insulin [18, 31, 32]. In addition, upon prolonged exposure to dietary fats, more dramatic outcomes may occur, such as defects in mitochondrial function [33, 34], anomalous regulation of autophagy [35, 36] and the ubiquitin/proteasome system [21] and, eventually, increased neuronal apoptosis [15]. …”

Hypothalamic inflammation and gliosis in obesity

“…With HFD feeding, mice accumulate a number of fatty acid species in the hypothalamus, including triacylglycerols, diacylglycerols and ceramides (34). Furthermore, acute intracerebroventricular (icv) infusion of lipids such as the saturated fatty acid palmitate and the ω-6 polyunsaturated arachidonate induces inflammatory signaling (11, 35–37), alters autophagic protection from cellular stress (38), increases the unfolded protein response in the endoplasmic reticulum (39, 40••), promotes insulin and leptin resistance (11, 41) and possibly triggers apoptosis (42). Likewise, lipid ingestion via milk fat gavage or butter-based HFD consumption increases the hypothalamic levels of saturated fatty acids and proinflammatory gene expression without evidence of systemic inflammation (15••, 17).…”