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Hypothalamic Lipotoxicity and Endoplasmic Reticulum Stress: a New Pathophysiological Mechanism of Obesity

Final Report Summary - OBERSTRESS (Hypothalamic Lipotoxicity and Endoplasmic Reticulum Stress: a New Pathophysiological Mechanism of Obesity)

Obesity and its related metabolic disorders are increasing at a rate that is considered of epidemic proportions in western and developing countries. The increasing prevalence of obesity is likely due to a combination of genetic predisposition, as well as evolutionary, social and environmental factors. Despite initial expectations, data gleaned over the last few years have uncovered the interaction between peripheral signals and brain targets provided by different neuropeptides and neurotransmitters. However, despite initial hope, this knowledge failed to provide as yet a much needed anti-obesity drug. It is generally felt that for progress in this area it is crucial to uncover the basic molecular mechanisms regulating energy homeostasis. Taking into account that almost all signalling proteins used by cells to communicate with its environment are assembled in the endoplasmic reticulum (ER), studies addressing the molecular mechanisms involved in ER functions have started to uncover the molecular mechanisms involved in some complex diseases.

The ER is a sophisticated luminal network in which protein synthesis, maturation, folding and transport take place. The term ER stress refers to the alterations of the protein folding functionality of the ER, which activates a complex signalling network termed the unfolded protein response (UPR), leading to coordinated transcriptional events promoting attenuation of protein synthesis, upregulation of ER folding machinery (a type of proteins called chaperones) and degradation of irreversibly misfolded proteins. Previous studies have demonstrated that ER stress and activation of UPR pathways play a major role promoting obesity-induced insulin resistance and type 2 diabetes in peripheral tissues. For example, inflammation, free lipid accumulation and hyperglycemia in pancreatic β cells and liver elicit activation of the UPR, leading to decreased mRNA insulin expression and inhibition of insulin signalling.

A current idea gaining credibility is that the adipose stores in some obese individuals become saturated and lipotoxic fat metabolites spill over into tissues not suited for lipid storage. Thus, accumulation of reactive lipid species, such as diacylglycerol (DAG), free fatty acids, free cholesterol and ceramides is a pathogenic mechanism of insulin resistance, type 2 diabetes, liver and cardiovascular disease. In peripheral tissues, such as β cell, skeletal muscle, liver and heart this process, known as lipotoxicity, occurs through inflammation and ER stress. However, despite this evidence, whether a) lipotoxocity may happen in the hypothalamus and, more specifically, whether b) lipotoxicity may induce hypothalamic ER stress or c) this mechanism is of relevance for obesity, is currently unknown. Therefore, the aims of this study were: 1) first, to determine whether central lipotoxic lipid species (such as ceramides) elicit ER stress in the hypothalamus and 2) second, to investigate whether that action accounts for the changes in energy balance associated to obesity and 3) third whether targeting hypothalamic ER stress mechanisms is a therapeutic strategy to prevent or revert obesity and its metabolic complications.