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1.  Association of Lipidome Remodeling in the Adipocyte Membrane with Acquired Obesity in Humans 
PLoS Biology  2011;9(6):e1000623.
The authors describe a new approach to studying cellular lipid profiles and propose a compensatory mechanism that may help maintain the normal membrane function of adipocytes in the context of obesity.
Identification of early mechanisms that may lead from obesity towards complications such as metabolic syndrome is of great interest. Here we performed lipidomic analyses of adipose tissue in twin pairs discordant for obesity but still metabolically compensated. In parallel we studied more evolved states of obesity by investigating a separated set of individuals considered to be morbidly obese. Despite lower dietary polyunsaturated fatty acid intake, the obese twin individuals had increased proportions of palmitoleic and arachidonic acids in their adipose tissue, including increased levels of ethanolamine plasmalogens containing arachidonic acid. Information gathered from these experimental groups was used for molecular dynamics simulations of lipid bilayers combined with dependency network analysis of combined clinical, lipidomics, and gene expression data. The simulations suggested that the observed lipid remodeling maintains the biophysical properties of lipid membranes, at the price, however, of increasing their vulnerability to inflammation. Conversely, in morbidly obese subjects, the proportion of plasmalogens containing arachidonic acid in the adipose tissue was markedly decreased. We also show by in vitro Elovl6 knockdown that the lipid network regulating the observed remodeling may be amenable to genetic modulation. Together, our novel approach suggests a physiological mechanism by which adaptation of adipocyte membranes to adipose tissue expansion associates with positive energy balance, potentially leading to higher vulnerability to inflammation in acquired obesity. Further studies will be needed to determine the cause of this effect.
Author Summary
Obesity is characterized by excess body fat, which is predominantly stored in the adipose tissue. When adipose tissue expands too much it stops storing lipid appropriately. The excess lipid accumulates in organs such as muscle, liver, and pancreas, causing metabolic disease. In this study, we aim to identify factors that cause adipose tissue to malfunction when it reaches its limit of expansion. We performed lipidomic analyses of human adipose tissue in twin pairs discordant for obesity—that is, one of the twins was lean and one was obese—but still metabolically healthy. We identified multiple changes in membrane phospholipids. Using computer modeling, we show that “lean” and “obese” membrane lipid compositions have the same physical properties despite their different compositions. We hypothesize that this represents allostasis—changes in lipid membrane composition in obesity occur to protect the physical properties of the membranes. However, protective changes cannot occur without a cost, and accordingly we demonstrate that switching to the “obese” lipid composition is associated with higher levels of adipose tissue inflammation. In a separate group of metabolically unhealthy obese individuals we investigated how the processes that regulate the “lean” and “obese” lipid profiles are changed. To determine how these lipid membrane changes are regulated we constructed an in silico network model that identified key control points and potential molecular players. We validated this network by performing genetic manipulations in cell models. Therapeutic targeting of this network may open new opportunities for the prevention or treatment of obesity-related metabolic complications.
doi:10.1371/journal.pbio.1000623
PMCID: PMC3110175  PMID: 21666801
2.  Cholesterol Induces Specific Spatial and Orientational Order in Cholesterol/Phospholipid Membranes 
PLoS ONE  2010;5(6):e11162.
Background
In lipid bilayers, cholesterol facilitates the formation of the liquid-ordered phase and enables the formation of laterally ordered structures such as lipid rafts. While these domains have an important role in a variety of cellular processes, the precise atomic-level mechanisms responsible for cholesterol's specific ordering and packing capability have remained unresolved.
Methodology/Principal Findings
Our atomic-scale molecular dynamics simulations reveal that this ordering and the associated packing effects in membranes largely result from cholesterol's molecular structure, which differentiates cholesterol from other sterols. We find that cholesterol molecules prefer to be located in the second coordination shell, avoiding direct cholesterol-cholesterol contacts, and form a three-fold symmetric arrangement with proximal cholesterol molecules. At larger distances, the lateral three-fold organization is broken by thermal fluctuations. For other sterols having less structural asymmetry, the three-fold arrangement is considerably lost.
Conclusions/Significance
We conclude that cholesterol molecules act collectively in lipid membranes. This is the main reason why the liquid-ordered phase only emerges for Chol concentrations well above 10 mol% where the collective self-organization of Chol molecules emerges spontaneously. The collective ordering process requires specific molecular-scale features that explain why different sterols have very different membrane ordering properties: the three-fold symmetry in the Chol-Chol organization arises from the cholesterol off-plane methyl groups allowing the identification of raft-promoting sterols from those that do not promote rafts.
doi:10.1371/journal.pone.0011162
PMCID: PMC2887443  PMID: 20567600

Results 1-2 (2)