Microbes may just be the next diet craze. Researchers have programmed bacteria to generate a molecule that, through normal metabolism, becomes a hunger-suppressing lipid. Mice that drank water laced with the programmed bacteria ate less, had lower body fat and staved off diabetes — even when fed a high-fat diet — offering a potential weight-loss strategy for humans.
The team will describe their approach in one of nearly 11,000 presentations at the 249th National Meeting & Exposition of the American Chemical Society (ACS), the world’s largest scientific society, taking place here through Thursday.
Obesity strongly increases the risk for developing several diseases and conditions, such as heart disease, stroke, type 2 diabetes and some types of cancer. One in three Americans is obese, and efforts to stem the epidemic have largely failed. Lifestyle changes and medication typically achieve only modest weight loss, and most people regain the weight. In recent years, numerous studies have shown that the population of microbes living in the gut may be a key factor in determining the risk for obesity and related diseases, suggesting that strategically altering the gut microbiome may impact human health.
One advantage to microbial medicine would be that it’s low maintenance, says Sean Davies, Ph.D. His goal is to produce therapeutic bacteria that live in the gut for six months or a year, providing sustained drug delivery. This is in contrast to weight-loss drugs that typically need to be taken at least daily, and people tend not to take their medications as directed over time. “So we need strategies that deliver the drug without requiring the patient to remember to take their pills every few hours,” Davies says.
For a therapeutic molecule, Davies and colleagues at Vanderbilt University selected N-acyl-phosphatidylethanolamines (NAPEs), which are produced in the small intestine after a meal and are quickly converted into N-acyl-ethanolamines (NAEs), potent appetite-suppressing lipids. The researchers altered the genes of a strain of probiotic bacteria so it would make NAPEs. Then they added the bacteria to the drinking water of a strain of mice that, fed a high-fat diet, develop obesity, signs of diabetes and fatty livers.
Compared to mice who received plain water or water containing control, non-programmed bacteria, the mice drinking the NAPE-making bacteria gained 15 percent less weight over the eight weeks of treatment. In addition, their livers and glucose metabolism were better than in the control mice. The mice that received the therapeutic bacteria remained lighter and leaner than control mice for up to 12 weeks after treatment ended.
In further experiments, Davies’ team found that mice that lacked the enzyme to make NAEs from NAPEs were not helped by the NAPE-making bacteria; but this could be overcome by giving the mice NAE-making bacteria instead. “This suggests that it might be best to use NAE-making bacteria in eventual clinical trials,” says Davies, especially if the researchers find that some people don’t make very much of the enzyme that converts NAPEs to NAEs. “We think that this would work very well in humans.”
The main obstacle to starting human trials is the potential risk that a treated person could transmit these special bacteria to another by fecal exposure. “We don’t want individuals to be unintentionally treated without their knowledge,” says Davies. “Especially because you could imagine that there might be some individuals, say the very young or old or those with specific diseases, who could be harmed by being exposed to an appetite-suppressing bacteria. So, we are working on genetically modifying the bacteria to significantly reduce its ability to be transmitted.”
The above story is based on materials provided by American Chemical Society.Note: Materials may be edited for content and length.
Ask people what it takes to live a long life, and they’ll say things like exercise, take Omega-3s, and see your doctor regularly.
Now research from Brigham Young University shows that loneliness and social isolation are just as much a threat to longevity as obesity.
“The effect of this is comparable to obesity, something that public health takes very seriously,” said Julianne Holt-Lunstad, the lead study author. “We need to start taking our social relationships more seriously.”
Loneliness and social isolation can look very different. For example, someone may be surrounded by many people but still feel alone. Other people may isolate themselves because they prefer to be alone. The effect on longevity, however, is much the same for those two scenarios.
The association between loneliness and risk for mortality among young populations is actually greater than among older populations. Although older people are more likely to be lonely and face a higher mortality risk, loneliness and social isolation better predict premature death among populations younger than 65 years.
“Not only are we at the highest recorded rate of living alone across the entire century, but we’re at the highest recorded rates ever on the planet,” said Tim Smith, co-author of the study. “With loneliness on the rise, we are predicting a possible loneliness epidemic in the future.”
The study analyzed data from a variety of health studies. Altogether, the sample included more than 3 million participants from studies that included data for loneliness, social isolation, and living alone.
Controlling for variables such as socioeconomic status, age, gender, and pre-existing health conditions, they found that the effect goes both ways. The lack of social connections presents an added risk, and the existence of relationships provides a positive health effect. The new study appears in Perspectives on Psychological Science.
Previous research from Holt-Lunstad and Smith puts the heightened risk of mortality from loneliness in the same category as smoking 15 cigarettes a day and being an alcoholic. This current study suggests that not only is the risk for mortality in the same category as these well-known risk factors, it also surpasses health risks associated with obesity.
“In essence, the study is saying the more positive psychology we have in our world, the better we’re able to function not just emotionally but physically,” Smith said.
There are many things that help to subdue the effects of loneliness. With the evolution of the internet, people can keep in contact over distances that they couldn’t before. However, the superficiality of some online experiences may miss emotional context and depth. Too much texting with each other can actually hurt a romantic relationship, for example. The authors of that texting study note, however, that saying something sweet or kind in a text is universally beneficial.
The above story is based on materials provided by Brigham Young University. Note: Materials may be edited for content and length.
There are many reasons why people gain different amounts of weight and why fat becomes stored in different parts of their bodies. Now, researchers point to a genetic reason for a tendency to put on weight.
Their findings, part of the largest genome wide study, were published in two papers today in the journalNature.
By analyzing genetic samples for over half a million individuals as part of the GIANT research project, which aims to identify genes that regulate human body and size, researchers found more than 100 locations across the genome that play roles in various obesity traits.
Learning more about the genes and biological processes may guide the development of weight-loss therapies, and help doctors tailor the health advice they give to patients.
“Our work clearly shows that predisposition to obesity and increased body mass index is not due to a single gene or genetic change,” says senior study authorElizabeth Speliotes, M.D., Ph.D., M.P.H, assistant professor of internal medicine and computational medicine and bioinformatics at the University of Michigan Health System.
“The large number of genes makes it less likely that one solution to beat obesity will work for everyone and opens the door to possible ways we could use genetic clues to help defeat obesity,” she says.
Speliotes and colleagues at Broad Institute of MIT and Harvard and Mt. Sinai Health System investigated the genetic basis of body mass index (BMI), a common measure of overall obesity, in up to 339,224 individuals.
Across the genome, which is the full set of a person’s genes, they found 97 sites associated with obesity. The number triples the number of previously known regions.
Once better understood, these genetic mechanisms may not only help to explain why not all of those who are obese develop related metabolic diseases, such as type 2 diabetes and high cholesterol, but could lead to possible ways to treat obesity or prevent metabolic diseases in those who are already obese.
“Presently we have no way of knowing if obese individuals will develop these obesity-related metabolic diseases and if so which ones,” says Speliotes, who is also a gastroenterologist at the U-M Health System. “We envision using these genetic markers to help doctors decide which treatments would work best to keep patients healthy.”
The analyses of genetic links to BMI indicate that the central nervous system has a role in obesity susceptibility, including a pathway that responds to changes in feeding and fasting and that is thought to be targeted by an FDA-approved weight-loss drug.
A cross-campus group of faculty and staff from the University of Michigan’s Department of Human Genetics, Department of Epidemiology, Kidney Epidemiology and Cost Center, Center for Statistical Genetics, Department of Biostatistics, Department of Internal Medicine, Department of Computational Medicine and Bioinformatics and the Institute for Social Research contributed to the papers.
Researchers from various institutions are increasingly bringing troves of DNA sequences into huge gene banks in hopes of tackling diseases.
The international GIANT consortium is already reaping the benefits of big data sets with papers on new variants linked to BMI and a companion paper in today’s Nature on waist-to-hip circumference ratio.
Belly fat key to health risk
In a companion study, an analysis of 224,459 individuals helped identify 49 sites in the genome associated with waist-to-hip ratio — a measure of body fat distribution. People with waistlines larger than hip circumferences have more belly fat surrounding their abdominal organs.
Accumulation of fat, especially around the stomach, increases the risk of cardiovascular and metabolic diseases.
Some sites display stronger effects in women than men, demonstrating that genetic regulation of body fat distribution varies between the sexes.
“We need to know these genetic locations because different fat depots pose different health risks,” says Karen Mohlke, Ph.D., professor of genetics at the University of North Carolina School of Medicine and a senior author on the paper that examined waist-to-hip ratio of fat distribution.
“If we can figure out which genes influence where fat is deposited, it could help us understand the biology that leads to various health conditions, such as insulin resistance/diabetes, metabolic syndrome, and heart disease.”
The above story is based on materials provided by University of Michigan Health System. Note: Materials may be edited for content and length.
In a breakthrough discovery, researchers at the University of Adelaide have revealed how damage from obesity is passed from a mother to her children, and also how that damage can be reversed.
The findings, by a team led by the University’s Robinson Research Institute, have major implications for the future of fertility research and are published today in the journal Development.
“It’s now well established that obesity in females leads to very serious fertility problems, including the inability to conceive. Obesity can also result in altered growth of babies during pregnancy, and it permanently programs the metabolism of offspring, passing the damage caused by obesity from one generation to the next,” says lead author Associate Professor Rebecca Robker from the Robinson Research Institute.
“In our laboratory studies, we’ve been able to unravel a key mechanism that leads to this multi-generational damage, and we’ve found a way to stop it happening,” Associate Professor Robker says.
The research team found that obesity leads to a particular stress response that causes damage to the mitochondria, which are critical energy-producing ‘organs’ within living cells.
“All of the mitochondria in our bodies come from our mother. If the mother is obese, this produces stresses that lead to reduced transmission of mitochondria to the offspring. We found that the eggs of such mothers lead to heavier-than-normal fetuses with greatly reduced amounts of mitochondrial DNA and other obvious signs of damage,” she says.
Having pinpointed the problem, Associate Professor Robker and her colleagues attempted to stop it from occurring.
“Once we had identified the type of stress involved, we used compounds known to alleviate that stress in the cells. In particular, we were interested in compounds that are also being tested in diabetes clinical trials,” Associate Professor Robker says.
“These compounds were highly successful in preventing the stress response, thereby stopping the damage from obesity being passed onto the offspring. It restored egg quality, embryo development and mitochondrial DNA to levels equivalent to those of a healthy mother. Effectively, the problem was fully reversed.”
Associate Professor Robker says the results of this work point towards a potential future therapy to restore “natural” fertility in obese women, and to prevent multi-generational damage passing onto their children.
“Importantly, this work further highlights that a woman’s nutritional state prior to getting pregnant matters greatly. Women are urged to eat healthy diets to optimise their chances for a healthy conception and to reduce the potential impact on their child’s future health,” she says.
The above story is based on materials provided by University of Adelaide. Note: Materials may be edited for content and length.
Mice gain weight even when fed normal amounts of food; similar mutation linked to severe obesity in humans
Boston, Mass., July 18, 2013 – Researchers at Boston Children’s Hospital have identified a genetic cause of severe obesity that, though rare, raises new questions about weight gain and energy use in the general obese population. The research, published in the journal Science on July 19, involved genetic surveys of several groups of obese humans and experiments in mice.
Mice with the genetic mutation gained weight even while eating the same amount of food as their normal counterparts; the affected gene, Mrap2, has a human counterpart (MRAP2) and appears to be involved in regulating metabolism and food consumption.
“These mice aren’t burning the fat, they’re somehow holding onto it,” says the study’s lead investigator Joseph Majzoub, MD, chief of endocrinology at Boston Children’s. “Mice with the genetic mutation gained more weight, and we found similar mutations in a cohort of obese humans.”
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The protein created by the Mrap2 gene appears to facilitate signaling to a receptor in the brain called Mc4r, which helps increase metabolism and decrease appetite as part of a larger signaling chain involved in energy regulation. Fat cells produce the hormone leptin, prompting receptors in the brain to instigate production of a second hormone, αMSH. Mc4r detects this hormone with the aid of Mrap2, leading to a decrease in appetite and weight. Mutations in this signaling chain, including mutations in Mc4r, are known to increase the likelihood of obesity.
Majzoub, first author Masato Asai, MD, PhD, now at Nagoya University in Japan, and colleagues studied mice with the Mrap2 gene knocked out both overall and just in the brain. In both cases, the mice grew to about twice their normal size. Weight gain was greatest when both copies of Mrap2 were knocked out, but the mice still showed weight gain and appetite increase with one working copy of the gene. The weight gain was more pronounced in males than females. In addition, the mice without Mrap2 had more exaggerated weight gain when fed a high-fat diet than normal mice.
Surprisingly, while the mice without Mrap2 didn’t eat more at first, they still gained weight faster than the controls. Later, their appetites increased and they continued to gain more weight than the controls, even when held to the same diet and quantity of food. In the end, the mutant mice had to be underfed by 10 to 15 percent to show the same weight gain as their normal peers. As soon as they were let off the restricted diet, their weight gain increased.
To investigate the gene in humans, Majzoub collaborated with Sadaf Farooqi, MD, PhD, of the University of Cambridge, and others to investigate groups of obese patients from around the world. The team found four mutations in the human equivalent of Mrap2 among the 500 people, all in patients with severe, early-onset obesity; each of the four affected patients had only one copy of the mutation.
While the finding suggests that these rare mutations directly cause obesity in less than 1 percent of the obese population, the researchers suspect that other mutations in the gene might occur more commonly and might interact with other mutations and environmental factors to cause more common forms of obesity. “We found other mutations that weren’t as clearly damaging to the gene,” notes Majzoub. “It’s possible that some of these more common mutations actually are pathogenic, especially in combination with other genes in the same pathway.”
One intriguing theory, called the thrifty-gene hypothesis, holds that rare mutations in genes like Mrap2 exist because they gave humans an evolutionary advantage in times of severe famine. Further investigation into how these mutations work may lend insight into the body’s mechanisms for energy storage and use. In the present study, the lab did not observe anything to explain why the mutant mice were storing more food energy, such as a difference in activity level or heat output.
Majzoub and his colleagues look forward to expanding the scope of the research, studying additional populations of obese people, including measures of their activity and diet, as well as further exploring how the gene alters energy balance.
The study was funded by the National Institutes of Health and other government, foundation and philanthropic grants. The team included researchers from Boston Children’s Hospital; the University of Cambridge and theNIHR Cambridge Biomedical Research Centre (UK); North Carolina State University; Queen Mary, University of London; Lund University (Sweden) and Steno Diabetes Center (Denmark); the Karolinksa Institute (Sweden); Harvard Medical School and the Broad Institute.
Editors note: Original article can be found here.
Credit: Boston Children’s Hospital