Ectopic fat accumulation in human astrocytes impairs insulin action.

Martin Heni,Harald Staiger,Martin Irmler,Martin Hrabě De Angelis,Anja Böhm,Norbert Hogrefe,Johannes Beckers,Sabine S Eckstein,Jens Schittenhelm,Hans-Ulrich Häring,Andreas Fritsche

doi:10.1098/rsos.200701

Abstract

Astrocytes provide neurons with structural support and energy in form of lactate, modulate synaptic transmission, are insulin sensitive and act as gatekeeper for water, ions, glutamate and second messengers. Furthermore, astrocytes are important for glucose sensing, possess neuroendocrine functions and also play an important role in cerebral lipid metabolism. To answer the question, if there is a connection between lipid metabolism and insulin action in human astrocytes, we investigated if storage of ectopic lipids in human astrocytes has an impact on insulin signalling in those cells. Human astrocytes were cultured in the presence of a lipid emulsion, consisting of fatty acids and triglycerides, to induce ectopic lipid storage. After several days, cells were stimulated with insulin and gene expression profiling was performed. In addition, phosphorylation of Akt as well as glycogen synthesis and cell proliferation was assessed. Ectopic lipid storage was detected in human astrocytes after lipid exposure and lipid storage was persistent even when the fat emulsion was removed from the cell culture medium. Chronic exposure to lipids induced profound changes in the gene expression profile, whereby some genes showed a reversible gene expression profile upon removal of fat, and some did not. This included FOXO-dependent expression patterns. Furthermore, insulin-induced phosphorylation of Akt was diminished and also insulin-induced glycogen synthesis and proliferation was impaired in lipid-laden astrocytes. Chronic lipid exposure induces lipid storage in human astrocytes accompanied by insulin resistance. Analyses of the gene expression pattern indicated the potential of a partially reversible gene expression profile. Targeting astrocytic insulin resistance by reducing ectopic lipid load might represent a promising treatment target for insulin resistance of the brain in obesity, diabetes and neurodegeneration.

Highlights

Studies have revealed the existence of insulin receptors throughout the brain [1,2] and shown that insulin has an important role in various brain functions such as control of body weight, food intake [3] and memory formation [4]
Human astrocytes form lipid droplets when exposed to fatty acids
To determine working concentrations for Lipofundin treatment that did not exert negative effects on cell viability, astrocytes were cultured with varying Lipofundin concentrations, and release of lactate dehydrogenase (LDH) into the medium was measured as marker for cell viability

Summary

Introduction

Studies have revealed the existence of insulin receptors throughout the brain [1,2] and shown that insulin has an important role in various brain functions such as control of body weight, food intake [3] and memory formation [4]. The central nervous system is sensitive to insulin in healthy humans, but can become insulin resistant in a number of conditions, including obesity, type 2 diabetes and neurodegenerative diseases [5]. Central nervous insulin resistance in overweight people leads to blunted postprandial satiety signals [7,8] and brain-derived regulation of peripheral insulin sensitivity is impaired in obese patients [9,10]. Brain insulin action was reduced in prefrontal cortex and hypothalamus of obese men, leading to an altered homeostatic set point and reduced inhibitory control, contributing to overeating behaviour [12]

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