CNIO Researchers Discover A New Gene Involved In Obesity

RAP1 is a gene that also protects telomeres. This is the first time that a link has been found between these structures that shorten with ageing and obesity

The discovery of an unexpected function for a gene that was associated to another process in the organism might be a solution in search of a problem, a clue to unsuspected connections. That is what has happened with RAP1, a gene that protects telomeres - the ends of chromosomes - after researchers from the Spanish National Cancer Research Centre (CNIO) surprisingly discovered its key role in obesity.

"We still don't know what evolutionary significance to attach to it, but it is at the very least interesting that a telomere gene is related to obesity", says Maria Blasco, CNIO director and co-author of the study published in the journal Cell Reports.

RAP1 forms part of the shelterin complex, a group of proteins that make up the protective hood of telomeres - the DNA sequence at the ends of chromosomes that shortens with each cellular division and thus measures the ageing of the organism. There are six shelterins, and CNIO's Telomeres & Telomerase Group, which studies them in-depth, has discovered that RAP1, contrary to the rest, is not essential for the survival of the organism; but that does not mean RAP1 is not important. The reverse is rather the case: when comparing the genomes of different species, it can be observed that RAP1 is the most conserved shelterin of all. Despite the long history of evolutionary changes, RAP1 has not changed; it is present even in yeast. This normally implies an important role in the organism, but which one?

CNIO researchers had discovered that RAP1, in addition to being located in telomeres, is also present in the rest of the chromosome; they supposed it acts regulating the action of other genes. In order to analyse this other potential function, and its importance in the organism, CNIO researchers created a lineage of mice without RAP1 and, to their surprise, discovered a model for obesity.

MICE LACKING RAP1 GAIN MORE WEIGHT

"Mice - especially female mice - without RAP1 do not eat more, but do gain weight. They suffer from metabolic syndrome, accumulate abdominal fat and present high glucose and cholesterol levels, amongst other symptoms", says Paula Martínez, first-author of the study.

The reason is that RAP1 plays an important role in the regulation of genes involved in metabolism. In particular, researchers have discovered that it acts on the same signalling pathway mediated by another protein: PPAR- gamma (PPAR-?). In fact, PPAR-? deficient mice suffer from a type of obesity "surprisingly similar" to that seen in mice without RAP1.

The next step in the research will be to study if RAP1 also plays a role in human obesity. "This discovery adds an element to the obesity equation, and opens up a possible new link between metabolic dysfunction and ageing, via a protein present in telomeres", says Blasco.

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Causal Relationship Between Adiposity And Heart Failure, And Elevated Liver Enzymes

New evidence supports a causal relationship between adiposity and heart failure, and between adiposity and increased liver enzymes, according to a study published this week in PLOS Medicine. The study, conducted by Inga Prokopenko, Erik Ingelsson, and colleagues from the ENGAGE (European Network for Genetic and Genomic Epidemiology) Consortium, also provides additional support for several previously shown causal associations such as those between adiposity and type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension.

The authors investigated whether adiposity is causally related to various cardiometabolic traits using a Mendelian randomization analysis, in which the variation in genes associated with conditions is used to assess the causal relationship between conditions. It is known that a genetic variant (rs9939609) within the genome region that encodes the fat-mass- and obesity-associated gene (FTO) is associated with increased BMI. Using genetic and health data collected in 36 population-based studies of nearly 200,000 individuals of European descent, the authors measured the strength of the causal association between BMI and cardiometabolic traits and found that higher BMI had a causal relationship with heart failure, type 2 diabetes, metabolic syndrome, dyslipidemia, hypertension, increased blood levels of liver enzymes, and several other cardiometabolic traits.

As with all Mendelian randomization studies, the reliability of the causal associations reported here depends on several assumptions made by the researchers. The authors report, "The present study addressing the role of BMI in 24 traits in up to 198,502 individuals provides novel insights in the causal effect of obesity on heart failure and increased liver enzymes levels."

They also say that this study "provides robust support to the causal relationship between obesity and a number of cardiometabolic traits reported previously. These results support global public prevention efforts for obesity in order to decrease cost and suffering from [type 2 diabetes] and heart failure."

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Obese Women Who Skip Breakfast At Greater Risk For Insulin Resistance

Overweight women who skip breakfast experience acute, or rapid-onset, insulin resistance, a condition that, when chronic, is a risk factor for diabetes, a new study finds. The results, which were presented at The Endocrine Society's 95th Annual Meeting in San Francisco, suggest that regularly skipping breakfast over time may lead to chronic insulin resistance and thus could increase an individual's risk for type 2 diabetes.

"Our study found that acute insulin resistance developed after only one day of skipping breakfast," said the study's lead author, Elizabeth Thomas, MD, an endocrinology fellow at the University of Colorado School of Medicine in Aurora.

In insulin resistance, a person requires more insulin to bring their glucose, or blood sugar, into a normal range, she explained.

Thomas and co-workers studied nine nondiabetic women, with an average age of 29, who were overweight or obese. The study took place on two days about a month apart. Subjects were randomly assigned to receive either breakfast or no breakfast at the first visit and the opposite at the second visit. Four hours later, all subjects ate the same standardized lunch at each visit. They had blood samples taken every 30 minutes after lunch for three hours to test their insulin and glucose levels.

It is normal for glucose levels to rise after eating a meal, which then triggers insulin production. The researchers found, however, that the women's insulin and glucose levels after lunch were significantly higher on the day they skipped breakfast than on the day when participants ate breakfast. The higher levels demonstrated acute insulin resistance because of skipping breakfast, according to Thomas.

It was not clear if this "heightened metabolic response" was temporary or lasting, but it may contribute to the development of chronic insulin resistance, she said. When the body becomes permanently resistant to the effects of the hormone insulin, sugar builds up in the blood, which can lead to prediabetes and diabetes over time.

"This information should help health care providers in counseling patients as to why it is better to eat a healthy, balanced breakfast than to skip breakfast," Thomas said.

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