a bio blog about genetics, genomics, and biotechnology
Posts Tagged ‘obesity’
With unprecedented levels of obesity across the Western world, and incidence of associated heart disease, cancer and diabetes rising, there is a major drive to find new treatments. Scientists from Germany have recently discovered that extracts of a traditional herbal remedy derived from Tabebuia impetiginosa can act to delay the absorption of dietary fat in animal models. They believe that the extract could be incorporated into a food supplement which may not only reduce obesity, but also lessen the risk of development of type 2 diabetes and coronary heart disease. Dr Nils Roos from the Max Rubner Institute will present the results on Monday 7th July at the Society for Experimental Biology’s Annual Meeting in Marseille.
Dr Roos and his team have shown that Tabebuia extract can reduce levels of triglycerides, a breakdown product of fat, in rats after they have been fed a fatty meal. “This result shows the extract may have a potential use in treating obesity,” he observes. “However, as coronary heart disease and diabetes have also been shown to be associated with higher triglyceride levels after eating, we believe a food-supplement based on Tabebuia could reduce the incidence of these diseases as well. What is more, as obesity in developing countries is also on the increase, such extracts, taken as a capsule or added to food, may be a cheaper alternative for the rural population to pharmaceuticals.”
Although it is clear that Tabebuia extract can act to inhibit the absorption of dietary fat, the scientists have not yet identified the exact compounds within the extract that are responsible for the effects. “The actual substances involved are probably even more active than the extract,” says Dr Roos. “We are currently in the process of identifying these compounds, and will then test long-term efficiacy and safety in miniature pigs whose physiology is closer to that of humans than rat physiology is, before moving onto human trials. At this point, we hope to be able to develop the extract, either as a food supplement or in a medicinal context.”
Source: Society for Experimental Biology
A small protein may have a big role in helping you make more bone and less fat, researchers say.
“The pathways are parallel, and the idea is if you can somehow disrupt the fat production pathway, you will get more bone,” says Dr. Xingming Shi, bone biologist at the Medical College of Georgia Institute of Molecular Medicine and Genetics.
He’s found the short-acting protein GILZ appears to make this desirable shift and wants to better understand how it does it with the long-term goal of targeted therapies for osteoporosis, obesity and maybe more.
“Osteoporosis and obesity are two major public health problems, but people have no idea whether they have a connection,” says Dr. Shi. Bone and fat do have a common source: both are derived from mesynchymal stem cells. Bone loss and fat gain also tend to happen with age and with use of the powerful, anti-inflammatory steroid hormones glucocorticoids. “When you age, your bone marrow microenvironment changes; the balance between the bone and fat pathway is broken,” says Dr. Shi, a faculty member in the MCG Schools of Medicine and Graduate Studies. “You have more fat cells accumulate.”
“The bones of elderly people or those who take glucocorticoids are yellow inside instead of red,” he says. And it gets worse: in a classic vicious cycle, the more fat, the more cytokines that stimulate production of bone-destroying osteoclasts and inhibit bone-forming osteoblasts. He recently showed that even the stem cells change with age: their numbers and their ability to differentiate decrease.
Weight gain and bone loss are established side effects of glucocorticoids, whose wide-ranging uses include treatment for arthritis, asthma, infections and organ transplants. Ironically, glucocorticoids also induce a short burst of GILZ. GILZ, in turn, inhibits the transcription factor PPARã2, called the master regulator of adipogenesis, or fat production, as well as CCAAT/enhancer-binding proteins that turn on this fat-producing gene. One way GILZ does this is by binding to the regulatory region of PPARã2, Dr. Shi has shown.
To restore a healthier balance of bone and fat production, sustained GILZ action is needed. “When you permanently express GILZ, cells cannot differentiate into fat cells. Instead, you increase bone formation. People like this idea,” says Dr. Shi, who has watched the mesynchymal stem cell production shift.
One point of controversy is that, at least in the lab, glucocorticoids seem to enhance bone formation. But Dr. Shi believes it’s the short burst of GILZ at work there. He wants to know exactly how it works to see if it could offer a targeted therapy for osteoporosis and obesity and maybe a safer option for many who need glucocorticoids.
A recent $1.5 million, five-year grant from the National Institute of Diabetes and Digestive and Kidney Diseases is enabling Dr. Shi to further test his hypothesis about how GILZ represses PPARã2 and to see if GILZ over-expression in mice reduces PPARã2 expression and consequently increases bone and decreases fat. A long-term goal is to understand exactly how PPARã2 controls fat and bone production.
GILZ also is a powerful immune and inflammation suppressor. It inhibits two key inflammatory molecules, NF-kB and AP-1, which turn on inflammatory genes in response to cytokines, such as TNF-á and IL-1â, involved in rheumatoid arthritis and other inflammatory diseases, Dr. Shi showed in research published on the cover of the April 15 issue of Journal of Cellular Biochemistry. That study notes GILZ’s potential as a novel anti-inflammatory therapy.
In fact, Dr. Shi believes GILZ is a key factor mediating the anti-inflammatory effects of glucocorticoids. A long-acting version of GILZ or a similar substance would be needed to produce, for example, a powerful new arthritis treatment minus the undesirable effects. About 50 percent of arthritis patients who take glucocorticoids develop osteoporosis, he notes, worsening an already difficulty condition worse.
People can’t take GILZ now, but another long-term goal is to develop a GILZ-like pill that would dramatically reduce fat production. Dr. Shi already has developed a cell line that continuously expresses GILZ.
Source: Medical College of Georgia
Researchers at the University of Minnesota have discovered a gene that may provide a clue as to why obesity rates increase with age. The research was published today in the Proceedings of the National Academy of Sciences.
Researchers in the lab of Kevin Wickman, Ph.D., associate professor of pharmacology at the University of Minnesota Medical School, removed a single gene from mice as part of an ongoing study to understand how the brain controls heart function. While some cardiac deficiencies were detected in these mice, the researchers unexpectedly found that these mice exhibited a predisposition to adult-onset obesity.
“This was not an outcome we expected, but now we have an animal model that may provide new insight into human obesity,” said Wickman, co-author of the article.
By examining closely where this gene, termed Girk4, is expressed in the body, the researchers found particularly high levels in the hypothalamus, a brain region involved in regulating food intake and energy expenditure. Wickman speculated that disruption of normal function in the hypothalamus may underlie the obesity seen in the mutant mice, but he acknowledges that more research is needed to understand where and how this gene works, and consequently, why mice missing this gene develop obesity.
The age-dependence of the obesity seen in this mouse model mimics human obesity patterns, researchers said. Indeed, the likelihood of people developing obesity more than doubles between the ages of 20 and 60.
“This is a novel finding that may provide important new insight to the underlying cellular mechanisms that influence obesity,” said Catherine Kotz, Ph.D., co-author of the article, scientist at the Minneapolis VA Medical Center and adjunct professor in the Department of Food Science and Nutrition at the University of Minnesota.
Source: University of Minnesota
Cydne A. Perry, Marco Pravetoni, Jennifer A. Teske, Carolina Aguado, Darin J. Erickson, Juan F. Medrano, Rafael Luján, Catherine M. Kotz, and Kevin Wickman. Predisposition to late-onset obesity in GIRK4 knockout mice. PNAS 2008 105: 8148-8153; published online on June 3, 2008, 10.1073/pnas.0803261105
Sometimes, the best discoveries in science are made by accident, though this isn’t exactly Nobel Prize worthy. Regardless, I’m still curious about the affects in humans and what the protein encoded by this gene normally does.
Whether you are fat or thin isn’t directly determined by your eating habits, suggest researchers who report new findings made in worms in the June issue of Cell Metabolism, a publication of Cell Press. While both feeding and fat in worms depends on serotonin levels in the nervous system, they found evidence that the nerve messenger acts through independent channels to control whether you eat versus what to do with those calories once you’ve eaten them.
“It says that the nervous system is a key regulator coordinating all energy-related processes through distinct molecular pathways,” said Kaveh Ashrafi of the University of California, San Francisco. “The nervous system makes a decision about its state leading to effects on behavior, reproduction, growth and metabolism. These outputs are related, but they are not consequences of each other. It’s not that feeding isn’t important, but the neural control of fat is distinct from feeding.”
If the results in worms can be extrapolated to humans, as Ashrafi suspects at a fundamental level they can given serotonin’s ancient evolutionary origins, then the finding may have clinical implications.
“From a clinical perspective, this may mean you could develop therapeutic strategies to manipulate fat metabolism independently of what you eat,” he said. “Now, the focus is primarily on feeding behavior. As important as that is, it’s only part of the story. If the logic of the system is conserved across species, a strategy that focuses solely on behavior can only go so far. It may be one reason diets fail.”
While fat regulation is at one level a relatively simple balance between energy intake and expenditure, the physiology is nonetheless quite complex, Ashrafi said. It was the researchers goal in the new study to dissect that complexity using the worm C. elegans, an organism that is much simpler to work with in comparison to mammals.
They found in the worms that control of feeding by serotonin involves receptors whose function is not required for fat control. Rather, the nerve messenger’s effects on fat depend on a separate neural channel and receptor that spark signals leading to the breakdown of fat. The byproducts of that process generated in fat then come “full circle” and control feeding behavior, Ashrafi said.
The findings show that, as in mammals, C. elegans feeding behavior depends on cues in the environment as well as internal cues. Moreover, the researchers said, “obesity and thinness are not solely determined by feeding behavior. Rather, feeding behavior and fat metabolism are coordinated but independent responses of the nervous system to the perception of nutrient availability.”
In both the worm C. elegans and in mammals, high serotonin levels are already known to lead to fat loss while low serotonin levels lead to fat accumulation, the researchers noted. However, there are some differences. In C. elegans, when serotonin goes up, feeding goes up and fat goes down. On the other hand, high serotonin leads people to eat less and shed fat.
Since C. elegans directly match their feeding rates to increasing and decreasing food concentrations, serotonin’s effects on fat and feeding in the worms are consistent with the nerve messenger’s role as a sensory gauge of nutrient availability, the researchers said. When resources are scarce, worms build up their fat reserves. Thus, the perception of food scarcity leads them to shift to a metabolic state favoring conservation of energy and the direction of nutrients to fat stores.
Despite those differences, Ashrafi said, given the contributions of the serotonin pathway to energy balance across species, “we speculate that human counterparts of feeding-independent fat regulatory genes identified in our study may similarly regulate energy balance.”
Source: Cell Press
Serotonin Regulates C. elegans Fat and Feeding through Independent Molecular Mechanisms. Supriya Srinivasan, Leila Sadegh, Ida C. Elle, Anne G.L. Christensen, Nils J. Faergeman, and Kaveh Ashrafi. Cell Metabolism. June, 2008: 7 (6).
I had no idea that serotonin played a role in food consumption and fat storage. I wonder if this is any reason why when people get depressed, they sometimes tend to eat a lot of “comfort foods”, since their serotonin levels are lower. This is of course just speculation.
New DNA variants found that can help to pile on the pounds
A study of 90,000 people has uncovered new genetic variants that influence fat mass, weight and risk of obesity. The variants act in addition to the recently described variants of the FTO gene: adults carrying variants in both genes are, on average, 3.8 kg (or 8.5 lb) heavier.
The variants map close to a gene called MC4R: mutations in this gene are the most common genetic cause of severe familial obesity. The study highlights the power of large collections of volunteer samples to uncover common variants that influence health.
“By working together with many international groups we have been able to assemble a sample collection which was large enough to allow this finding to be made,” explains Dr Ruth Loos, leading author from the Medical Research Council Epidemiology Unit. “Several groups had shown that rare, highly disruptive variants in the MC4R gene were responsible for very severe, genetic forms of obesity: this collaboration has uncovered more common variants that affect more people.”
The study, published in Nature Genetics, is led by investigators from the Cambridge GEM consortium (Genetics of Energy Metabolism) and Oxford University and is a collaboration between 77 institutions from the UK, USA, France, Germany, Italy, Finland and Sweden.
The team studied more than 77,000 adults and found that two copies of genetic variants resulted in an average increase in weight of about 1.5 kg.
This is the second set of common variants that are associated with weight and obesity, following the study, involving many of the same team, published in April 2007 that uncovered a role for the FTO gene. People who carry two copies of an FTO variant are about 2-3 kg heavier than those who have no copies of the variant.
Importantly, the effects of the new gene add to those of FTO; people who carried both the FTO variant and new variants were on average 3.8 kg (8.5 lb) heavier.
“This is a great example of how cooperation can bring about new findings that can be missed when researchers work in isolation,” explains Dr Inês Barroso, Investigator at the Wellcome Trust Sanger Institute and one of the senior authors on the study. “The precise role in obesity of genetic variants in FTO and near MC4R remains to be discovered, but we can now begin to understand the biological consequences of these variants. This is where this research will make a difference.”
MC4R protein plays a pivotal role in many aspects of physiology, including regulation of appetite and energy expenditure. The severe form of MC4R-related obesity is a consequence of alterations in the gene sequence, resulting in an inactive or less active MC4R protein.
By contrast, the new variants lie some distance from the MC4R gene. The team suspect that the sequence variant changes activity of the MC4R gene, perhaps by disrupting DNA regions required for normal activity of MC4R.
“Through this new and powerful genetic approach we are increasingly finding that the genes known to play a role in severe – but rare – diseases are also implicated in much more common disease,” explains Professor Mark McCarthy, Robert Turner Professor of Diabetes at the University of Oxford, UK. “The common variants we are uncovering do not have such a dramatic effect on the normal functioning of the gene as do the rare mutations in MC4R that can cause rare examples of very serious, early onset obesity.”
Dramatically, in a study of almost 6000 children, they found that the effects were almost double those seen in adults. Between the ages of four and seven, this additional increase in weight was the result, almost exclusively, of gain of fat tissue, and not due to gain in muscle or other solid tissues.
This more dramatic effect in young children reflects the more extreme consequences seen with rare variants of MC4R that severely disrupt its activity, suggesting that the novel variants do indeed exert their effect through action on MC4R.
“Our work to understand common disease, such as obesity, depends on the participation of thousands of people – members of the public who provide samples,” explains Professor Nick Wareham, Director of the MRC Epidemiology Unit. “Without their willing participation, we could never achieve the power in our research to make striking findings like this.
“For each discovery, our efforts and the contribution of the participants will lead to improved healthcare for the population at large.”
The team will now look to uncover how the DNA variants affect activity of the MC4R protein, which is a key player in orchestrating information from the body to control appetite and energy expenditure to keep body weight in balance. The team propose that altered activity of MC4R, imposed by the variants, might reduce its ability to carry out this important role.
The team emphasize that, although gene variants can affect weight, body mass index and obesity, they are only part of the story: lifestyle actions such as good diet and regular exercise are vital to control of weight.
Source: Wellcome Trust Sanger Institute
Loos RJF et al. (2008) Association studies involving over 90,000 people demonstrate that common variants near to MC4R influence fat mass, weight and risk of obesity. Nature Genetics Published online on Sunday 4 May 2008.
Obesity is more than a cosmetic concern because it increases a person’s risk for developing high blood pressure, diabetes and many other serious health problems. It’s well understood that consuming more calories than you expend through exercise and daily activities causes weight gain. But with about one in every three American adults now considered obese, researchers are attempting to identify additional factors that affect a person’s tendency to gain and retain excess weight. In the April issue of Mayo Clinic Proceedings, researchers from Mayo Clinic Arizona and Arizona State University examine the role that bacteria in the human gastrointestinal tract play in regulating weight and the development of obesity.
Known as gut microbiota, the trillions of bacteria that populate the human gastrointestinal tract perform a variety of chores. These “friendly” microbes help extract calories from what we eat, help store these calories for later use, and provide energy and nutrients for the production of new bacteria to continue this work. … Continue Reading »
The brain can sense the calories in food, independent of the taste mechanism, researchers have found in studies with mice. Their finding that the brain’s reward system is switched on by this “sixth sense” machinery could have implications for understanding the causes of obesity. For example, the findings suggest why high-fructose corn syrup, widely used as a sweetener in foods, might contribute to obesity. … Continue Reading »