Posts tagged triglycerides
Articles and news from the latest research reports.
Scientists Shed Light on Cause of Spastic Paraplegia
Scientists at The Scripps Research Institute (TSRI) have discovered that a gene mutation linked to hereditary spastic paraplegia, a disabling neurological disorder, interferes with the normal breakdown of triglyceride fat molecules in the brain. The TSRI researchers found large droplets of triglycerides within the neurons of mice modeling the disease.
The findings, reported this week online ahead of print by the journal Proceedings of the National Academy of Sciences, point the way to potential therapies and showcase an investigative strategy that should be useful in determining the biochemical causes of other genetic illnesses. Scientists in recent decades have linked thousands of gene mutations to human diseases, yet many of the genes in question code for proteins of unknown function.
“We often need to understand the protein function that is disrupted by a gene mutation, if we’re going to understand the mechanistic basis for the disease and move towards developing a therapy, and that is what we’ve tried to do here,” said Benjamin F. Cravatt, professor and chair of TSRI’s Department of Chemical Physiology.
There is currently no treatment for hereditary spastic paraplegia (HSP), a set of genetic illnesses whose symptoms include muscle weakness and stiffness, and in some cases cognitive impairments. About 100,000 people worldwide live with HSP.
Uncovering Clues
In the new study, Cravatt and members of his laboratory, including graduate student Jordon Inloes and postdoctoral fellow Ku-Lung Hsu, focused on DDHD2, an enzyme of unclear function whose gene is mutated in a subset of HSP cases. “These cases involving DDHD2 disruption feature cognitive defects as well as spasticity and muscle wasting, so they’re among the more devastating forms of this illness,” said Cravatt.
To start, the researchers created a mouse model of DDHD2-related HSP, in which a targeted deletion from the DDHD2 gene eliminated the expression of the DDHD2 protein. “These mice showed symptoms similar to those of HSP patients, including abnormal gait and lower performance on tests of movement and cognition,” said Inloes.
Prior research had suggested that the DDHD2 enzyme is expressed in the brain and is involved somehow in lipid metabolism. One study reported elevated levels of an unknown fat molecule in the brains of DDHD2-mutant HSP patients. Cravatt’s team compared the tissues of the no-DDHD2 mice to the tissues of mice with normal versions of the gene, and also found that the mutant mice had much higher levels of a type of fat molecule, principally in the brain.
Using a set of sophisticated “lipidomics” tests to analyze the accumulating fat molecules, they identified them as triglycerides—a major component of stored fat in the body, and a risk factor for obesity, atherosclerosis and type 2 diabetes.
“We were able to show as well, using both light microscopy and electron microscopy, that droplets of triglyceride-rich fat are present in the neurons of DDHD2-knockout mice, in several brain regions, but are not present in normal mice,” said Inloes.
For the next phase of the study, Cravatt’s team developed a complementary tool for studying DDHD2’s function: a specific inhibitor of the DDHD2 enzyme, one of a set of powerful enzyme-blocking compounds they had identified in a study reported last year. “After four days of treatment with this inhibitor, normal mice showed an increase in brain triglycerides,” said Inloes. “This suggests that DDHD2 normally breaks down triglycerides, and its inactivity allows triglycerides to build up.”
Finally the team confirmed DDHD2’s role in triglyceride metabolism by showing that triglycerides are rapidly broken down into smaller fatty acids in its presence.
“These findings give us some insight, at least, into the biochemical basis of the HSP syndrome,” said Cravatt.
Looking Ahead
Future projects in this line of inquiry, he adds, include a study of how triglyceride droplets in neurons lead to impairments of movement and cognition, and research on potential therapies to counter these effects, including the possible use of diacylglycerol transferase (DGAT) inhibitors, which reduce the natural production of triglycerides.
Cravatt also notes that the same approach used in this study can be applied to other enzymes in DDHD2’s class (serine hydrolases), whose dysfunctions cause human neurological disorders.
(Source: scripps.edu)
(Image caption: A cross-section of mouse brain in the nucleus accumbens, a region of the brain known to be involved in reward and motivation, taken by a fluorescence microscope. Blue corresponds to cell nuclei, and green to fluorescence emitted by a green-fluorescent protein (NdT: the original incorrectly states “green fluorescente protein”) that identifies neurons having received the virus that can genetically abolish the expression of lipoprotein lipase protein. Credit: ©Serge Luquet, CNRS/Université Paris Diderot)
Obesity: are lipids hard drugs for the brain?
Why can we get up for a piece of chocolate, but never because we fancy a carrot? Serge Luquet’s team at the “Biologie Fonctionnelle et Adaptative” laboratory (CNRS/Université Paris Diderot) has demonstrated part of the answer: triglycerides, fatty substances from food, may act in our brains directly on the reward circuit, the same circuit that is involved in drug addiction. These results, published on April 15, 2014 in Molecular Psychiatry, show a strong link in mice between fluctuations in triglyceride concentration and brain reward development. Identifying the action of nutritional lipids on motivation and the search for pleasure in dietary intake will help us better understand the causes of some compulsive behaviors and obesity.
Though the act of eating responds to a biological need, it is also an essential cultural and social function in our modern societies. Meals are generally associated with a strong notion of pleasure, a feeling that pushes us towards food. Sometimes this is dangerous: 2.8 million people worldwide die from the consequences of obesity each year. Fundamentally, obesity is caused by imbalance between calories consumed and expended. A sedentary life combined with an abundance of sugary, fatty foods provides fertile ground for this disease.
The body uses sugars and fats as energy sources. The brain only consumes glucose. So why do we find an enzyme that can decompose triglycerides, lipids that come in particular from food, at its core, at the heart of the reward mechanism? A team at the “Biologie Fonctionnelle et Adaptative” laboratory (CNRS/Université Paris Diderot) led by Serge Luquet, a CNRS researcher, has tackled this fundamental question.
If they have the choice, normal behavior in mice is to prefer a high-fat diet to simpler foods. To simulate the action of a good meal, researchers have developed an approach that allows small quantities of lipids to be injected directly into the brains of mice. They observed that an infusion of triglycerides in the brain reduces the animal’s motivation to press a lever to obtain a food reward. It also reduces physical activity by half. What is more, an “infused” mouse balances its diet between the two food sources offered (high-fat foods and simpler foods).
To ensure that it is indeed the lipids injected that change the mice’s behavior, these Parisian scientists made sure that the lipids could not be detected by the animal’s brain any longer. They managed to remove the specific enzyme for triglycerides by silencing its coding gene, but only at the heart of the reward mechanism. The animal then shows increased motivation to obtain a reward, and if given the choice, consumes much richer food than average. This work echoes the previous work by their colleagues: reducing this enzyme in the hippocampus causes obesity.
Paradoxically, with obesity, blood (and therefore brain) triglyceride levels are higher than average. So obesity is often associated with overconsumption of sugary, fatty foods. The researchers explain this: with long-lasting high exposure to triglycerides, mice always display lower locomotor activity. By contrast, food rewards are still attractive! The ideal conditions for weight gain are therefore in place. At high triglyceride contents, the brain adapts to obtain its reward, similar to the mechanisms observed when people consume drugs.
This work, financed in particular by CNRS and ANR, indicate for the first time that triglycerides from food may act as hard drugs in the brain, on the reward system, controlling the motivational and pleasureseeking component of food intake.