Metabolic Alterations and Increased Liver mTOR Expression Precede the Development of Autoimmune Disease in a Murine Model of Lupus Erythematosus

Laia Vilà,Núria Roglans,Juan C Laguna,Miguel Baena,Emma Barroso,Manuel Merlos,Marta Alegret

doi:10.1371/journal.pone.0051118

Abstract

Although metabolic syndrome (MS) and systemic lupus erythematosus (SLE) are often associated, a common link has not been identified. Using the BWF1 mouse, which develops MS and SLE, we sought a molecular connection to explain the prevalence of these two diseases in the same individuals. We determined SLE- markers (plasma anti-ds-DNA antibodies, splenic regulatory T cells (Tregs) and cytokines, proteinuria and renal histology) and MS-markers (plasma glucose, non-esterified fatty acids, triglycerides, insulin and leptin, liver triglycerides, visceral adipose tissue, liver and adipose tissue expression of 86 insulin signaling-related genes) in 8-, 16-, 24-, and 36-week old BWF1 and control New-Zealand-White female mice. Up to week 16, BWF1 mice showed MS-markers (hyperleptinemia, hyperinsulinemia, fatty liver and visceral adipose tissue) that disappeared at week 36, when plasma anti-dsDNA antibodies, lupus nephritis and a pro-autoimmune cytokine profile were detected. BWF1 mice had hyperleptinemia and high splenic Tregs till week 16, thereby pointing to leptin resistance, as confirmed by the lack of increased liver P-Tyr-STAT-3. Hyperinsulinemia was associated with a down-regulation of insulin related-genes only in adipose tissue, whereas expression of liver mammalian target of rapamicyn (mTOR) was increased. Although leptin resistance presented early in BWF1 mice can slow-down the progression of autoimmunity, our results suggest that sustained insulin stimulation of organs, such as liver and probably kidneys, facilitates the over-expression and activity of mTOR and the development of SLE.

Highlights

From the second half of the twentieth century onwards, there has been a growth in the prevalence of two apparently unrelated pathologic conditions, namely metabolic and autoimmune diseases, especially in affluent western societies [1,2,3,4,5]
The percentage of CD4+CD25+ T cells was increased at week 8 (x1.4 fold vs CT values, Figure 2C), and the percentage of CD4+CD25+FoxP3 T cells increased in Systemic lupus erythematosus (SLE) mice at week 8 (x1.4 fold vs CT values) and 16 (x1.16 fold vs CT values) (Figure 2D)
We used a murine model of SLE, which, like humans with this autoimmune disease, shows the classical manifestations of metabolic syndrome (MS)

Summary

Introduction

From the second half of the twentieth century onwards, there has been a growth in the prevalence of two apparently unrelated pathologic conditions, namely metabolic and autoimmune diseases, especially in affluent western societies [1,2,3,4,5] This occurrence has coincided with a drastic change in life style, involving massive adoption of sedentary practices associated with dietary habits skewed towards the consumption of high caloric density, nutrient poor foods, which promote a marked positive energy balance in the general population [6,7]. Those who die early in the course of SLE have active disease and a high incidence of infection associated with treatment with large doses of corticosteroids, while most patients who die later in the course of the disease, the most common situation nowadays, die from myocardial infarction [9,10]

Methods

Results

Conclusion