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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.  Global Transcript Profiles of Fat in Monozygotic Twins Discordant for BMI: Pathways behind Acquired Obesity  
PLoS Medicine  2008;5(3):e51.
Background
The acquired component of complex traits is difficult to dissect in humans. Obesity represents such a trait, in which the metabolic and molecular consequences emerge from complex interactions of genes and environment. With the substantial morbidity associated with obesity, a deeper understanding of the concurrent metabolic changes is of considerable importance. The goal of this study was to investigate this important acquired component and expose obesity-induced changes in biological pathways in an identical genetic background.
Methods and Findings
We used a special study design of “clonal controls,” rare monozygotic twins discordant for obesity identified through a national registry of 2,453 young, healthy twin pairs. A total of 14 pairs were studied (eight male, six female; white), with a mean ± standard deviation (SD) age 25.8 ± 1.4 y and a body mass index (BMI) difference 5.2 ± 1.8 kg/m2. Sequence analyses of mitochondrial DNA (mtDNA) in subcutaneous fat and peripheral leukocytes revealed no aberrant heteroplasmy between the co-twins. However, mtDNA copy number was reduced by 47% in the obese co-twin's fat. In addition, novel pathway analyses of the adipose tissue transcription profiles exposed significant down-regulation of mitochondrial branched-chain amino acid (BCAA) catabolism (p < 0.0001). In line with this finding, serum levels of insulin secretion-enhancing BCAAs were increased in obese male co-twins (9% increase, p = 0.025). Lending clinical relevance to the findings, in both sexes the observed aberrations in mitochondrial amino acid metabolism pathways in fat correlated closely with liver fat accumulation, insulin resistance, and hyperinsulinemia, early aberrations of acquired obesity in these healthy young adults.
Conclusions
Our findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.
Leena Peltonen and colleagues uncover the metabolic changes that result from obesity through an analysis of genetically identical twin pairs in which one was obese and the other was not.
Editors' Summary
Background.
Around the world, the proportion of people who are obese (people with an unhealthy amount of body fat) is increasing. In the US, for example, 1 adult in 7 was obese in the mid 1970s. That is, their body mass index (BMI)—their weight in kilograms divided by their height in meters squared—was more than 30. Nowadays, 1 US adult in 3 has a BMI this high and, by 2025, it is predicted that 1 in 2 will be obese. This obesity epidemic is being driven by lifestyle changes that encourage the over-consumption of energy-rich foods and discourage regular physical activity. The resultant energy imbalance leads to weight gain (the excess energy is stored as body fat or adipose tissue) and also triggers numerous metabolic changes, alterations in the chemical processes that convert food into the energy and various substances needed to support life. These obesity-related metabolic changes increase a person's risk of developing adverse health conditions such as diabetes, a condition in which dangerously high levels of sugar from food accumulate in the blood.
Why Was This Study Done?
The changes in human fat in obesity have not been completely understood, although the abnormal metabolism of adipose tissue is increasingly seen as playing a critical part in excessive weight gain. It has been very difficult to decipher which molecular and metabolic changes associated with obesity are the result of becoming obese, and which might contribute towards the acquisition of obesity in humans in the first place. To discover more about the influence of environment on obesity-induced metabolic changes, the researchers in this study have investigated these changes in pairs of genetically identical twins.
What Did the Researchers Do and Find?
The researchers recruited 14 pairs of genetically identical Finnish twins born between 1975 and 1979 who were “obesity discordant”—that is, one twin of each pair had a BMI of about 25 (not obese); the other had a BMI of about 30 (obese). The researchers took fat and blood samples from each twin, determined the insulin sensitivity of each, and measured the body composition and various fat stores of each. They found that the obese twins had more subcutaneous, intra-abdominal, and liver fat and were less insulin sensitive than the non-obese twins. Insulin sensitivity correlated with the amount of liver fat. Analysis of gene expression in the fat samples showed that 19 gene pathways (mainly inflammatory pathways) were expressed more strongly (up-regulated) in the obese twins than the non-obese twins, whereas seven pathways were down-regulated. The most highly down-regulated pathway was a mitochondrial pathway involved in amino acid breakdown, but mitochondrial energy metabolism pathways were also down-regulated. Finally, mitochondrial DNA copy number in fat was reduced in the obese twins by nearly half, a novel observation that could partly account for the obesity-induced metabolic defects of these individuals.
What Do These Findings Mean?
These and other findings identify several pathways that are involved in the development of obesity and insulin resistance. In particular, they suggest that changes in mitochondrial energy production pathways and in mitochondrial amino acid metabolism pathways could play important roles in the development of obesity and of insulin resistance and in the accumulation of liver fat even in young obese people. The study design involving identical twins has here produced some evidence for aberrations in molecules critical for acquired obesity. The results suggest that careful management of obesity by lifestyle changes has the potential to correct the obesity-related metabolic changes in fat that would otherwise lead to diabetes and other adverse health conditions in obese individuals. In addition, they suggest that the development of therapies designed to correct mitochondrial metabolism might help to reduce the illnesses associated with obesity.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050051.
The MedlinePlus encyclopedia has pages on obesity and diabetes (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on all aspects of obesity (in English and Spanish)
The UK National Health Service's health Web site (NHS Direct) provides information about obesity
The International Obesity Taskforce provides information about preventing obesity and on diabetes and obesity
The UK Foods Standards Agency and the United States Department of Agriculture provide online tools and useful advice about healthy eating for adults and children
Information is available for patients and carers from the US National Diabetes Information Clearinghouse on diabetes, including information on insulin resistance
doi:10.1371/journal.pmed.0050051
PMCID: PMC2265758  PMID: 18336063

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