Archive for the ‘Loss fat’ Category

Molecular switch found in mice could lead to future obesity treatments, scientists say

A surprise discovery — that calorie-burning brown fat can be produced experimentally from muscle precursor cells in mice — raises the prospect of new ways to fight obesity and overweight, say scientists from Dana-Farber Cancer Institute.

Reporting in the Aug. 21 issue of the journal Nature, the researchers demonstrated that brown fat, which is known as the “good” form of fat — so called because it burns calories and releases energy, unlike “bad” white fat that simply stores extra calories — can be generated from unspecialized precursors that routinely spawn skeletal muscle.

The team led by Dana-Farber’s Bruce Spiegelman, PhD, showed that a previously known molecular switch, PRDM16, regulates the creation of brown fat from immature muscle cells. They also determined that the process is a two-way street: Knocking out PRDM16 in brown fat cells can convert them into muscle cells. However, Spiegelman called the latter an “experimental lab trick” for which he currently envisions no practical applications.

The “huge surprise” of the study results, he said, was that muscle precursor cells known as “satellite cells” are able to give birth to brown fat cells under the control of PRDM16.

Spiegelman said the finding confirms that PRDM16 is the “master regulator” of brown fat development. The confirmation will spur ongoing research in his laboratory, he said, to see if drugs that rev up PRDM16 in mice — and potentially, in people — could convert white fat into brown fat and thereby treat obesity. Another strategy, he said, might be to transplant brown fat cells into an overweight person to turn on the calorie-burning process.

“I think we now have very convincing evidence that PRDM16 can turn cells into brown fat cells, with the possibility of combating obesity,” said Spiegelman, the senior author of the paper. The lead author is Patrick Seale, PhD, a postdoctoral fellow in the Spiegelman lab.

Another paper in the same issue of Nature described a different trigger of brown fat production, a molecule called BMP7. A commentary in the journal by Barbara Cannon, an internationally recognized researcher in the biology of fat cells at the University of Stockholm, said that the two reports “take us a step closer to the ultimate goal of promoting the brown fat lineage as a potential way of counteracting obesity.”

The Spiegelman group has long studied fat cells both as a model for normal and abnormal cell development, which relates to cancer, and also because fat cells play such a key role in the growing epidemics of obesity and diabetes.

There is much interest in brown fat’s role in regulating metabolism. Rodents and human infants have abundant brown fat that dissipates food energy as heat to protect against the cold. Though human adults have little brown fat, it apparently does have a metabolic function, including the potential to be amplified in some way to combat obesity.

In 2007, Spiegelman and colleagues reported they had inserted PRDM16 genes into white fat precursors, which they implanted under the skin of mice. The PRDM16 switch coaxed the white fat precursors to produce brown fat cells instead of white. To Spiegelman, this suggested the possibility of transplanting PRDM16-equipped white fat precursors into people who are at high risk of becoming obese, to shift their metabolism slightly into a calorie-burning mode.

The new research adds another potential source of brown fat — the muscle cell progenitors, or myoblasts, that exist in the body to replace mature muscle cells as needed. The progenitors, which can be thought of as “adult stem cells,” are committed to becoming specialized muscle cells when activated by appropriate signals, or, as the study revealed, brown fat cells when PDRM16 is turned on. The PRDM16 trigger “is very powerful at what it does,” said Spiegelman, who is also a professor of cell biology at Harvard Medical School.

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Article adapted by MD Sports from original press release.
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Contact: Bill Schaller
Dana-Farber Cancer Institute 

Other authors of the paper include Bryan Bjork, PhD, and David R. Beier, PhD, MD, of Brigham and Women’s Hospital; Michael Rudnicki, PhD, of the Ottawa Health Research Institute; and Hediye Erdjument-Bromage, PhD, and Paul Tempst, PhD, of Memorial Sloan-Kettering Cancer Center.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.

Researchers at Albert Einstein College of Medicine of Yeshiva University have discovered a process that controls the amount of fat that cells store for use as a back-up energy source. Disruption of this process allows cellular fat to accumulate — a key factor in age-related metabolic diseases such as obesity and type 2 diabetes. The study is published today in the online version of Nature.

Discovery of this previously unknown fat-fighting pathway could lead to novel drugs for the treatment of metabolic syndrome (characterized by obesity, blood lipid disorders, and insulin resistance) and for a common liver disease known as “fatty liver” or steatohepatitis. Nonalcoholic steatohepatitis (NASH) is a common, often “silent” liver disease. Although NASH resembles alcoholic liver disease, it occurs in people who drink little or no alcohol. NASH affects 2 to 5 percent of Americans, according to the National Institute of Diabetes and Digestive and Kidney Diseases.

All cells store lipids, a type of fat, in the form of small droplets that can be broken down for energy when needed. In situations of excessive food intake or in certain diseases such as diabetes or obesity, these lipid droplets become so large that they interfere with normal cell function.

“In this study, we found that the amount of fat stored in these intracellular lipid droplets is controlled through autophagy, a process until now thought to help primarily in digesting and recycling damaged cellular structures,” says Mark Czaja, M.D., professor of medicine at Einstein whose team worked collaboratively on the research with the laboratory of Ana Maria Cuervo, M.D., Ph.D., associate professor of developmental & molecular biology, medicine, and anatomy & structural biology at Einstein.

Autophagy, or “self-eating,” is carried out by lysosomes, which function as the cell’s recycling center. In studies of liver cells in culture and in live animals, Dr. Czaja and his colleagues discovered that lysosomes do something never before observed: continuously remove portions of lipid droplets and process them for energy production.

“When food is scarce, autophagy becomes a main source of energy for the cells and this process of digesting lipid droplets is accelerated,” says Dr. Cuervo. “If autophagy slows down, as occurs in aging, the lipid droplets stored in cells keep growing and eventually become so big that they can no longer be degraded.”

This slowdown in fat control appears to trigger a vicious cycle in which the enlarging fat droplets impair autophagy, allowing even more fat to accumulate, and so on, which could eventually contribute to diseases such as diabetes. The researchers noted that therapies aimed at helping autophagy operate more efficiently might prevent disease by keeping fat droplets under control.

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Article adapted by MD Sports from original press release.
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Contact: Deirdre Branley
Albert Einstein College of Medicine

Drs. Cuervo and Czaja’s paper, “Autophagy regulates lipid metabolism” is published in the April 1 online version of Nature. Their co-authors at Einstein include Rajat Singh and Susmita Kaushik (primary co-authors), Yongjun Wang, Youqing Xiang, and Inna Novak; as well as Masaaki Komatsu and Keiji Tanaka of the Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo, Japan.

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About Albert Einstein College of Medicine of Yeshiva University

Albert Einstein College of Medicine of Yeshiva University is one of the nation’s premier centers for research, medical education and clinical investigation. It is the home to some 2,000 faculty members, 750 M.D. students, 350 Ph.D. students (including 125 in combined M.D./Ph.D. programs) and 380 postdoctoral investigators. Last year, Einstein received more than $130 million in support from the NIH. This includes the funding of major research centers at Einstein in diabetes, cancer, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Through its extensive affiliation network involving five hospital centers in the Bronx, Manhattan and Long Island – which includes Montefiore Medical Center, The University Hospital and Academic Medical Center for Einstein – the College runs one of the largest post-graduate medical training program in the United States, offering approximately 150 residency programs to more than 2,500 physicians in training. For more information, please visit http://www.aecom.yu.edu.

By studying the genes of a German child born with unusually well developed muscles, an international research team has discovered the first evidence that the gene whose loss makes “mighty mice” also controls muscle growth in people.

Writing in the June 24 issue of the New England Journal of Medicine, German neurologist Markus Schuelke, M.D., and the team show that the child’s extra-large muscles are due to an inherited mutation that effectively silences the myostatin gene, proving that its protein normally keeps muscle development in check in people.

People with muscle-wasting conditions such as muscular dystrophy, and others just wanting to “bulk up,” have eagerly followed work on myostatin, hoping for a way to counteract the protein’s effects in order to build or rebuild muscle mass. But while research with mice has continued to reveal myostatin’s role and the effects of interfering with it, no one knew whether any of the results would be relevant to humans.

“This is the first evidence that myostatin regulates muscle mass in people as it does in other animals,” says Se-Jin Lee, M.D., Ph.D., professor of molecular biology and genetics in the Institute for Basic Biomedical Sciences at Johns Hopkins and co-author on the study. “That gives us a great deal of hope that agents already known to block myostatin activity in mice may be able to increase muscle mass in humans, too.”

Lee and his team discovered in 1997 that knocking out the myostatin gene led to mice that were twice as muscular as their normal siblings, lending them the moniker “mighty mice.” Later, others showed that naturally bulky cattle, such as Belgian Blues, got their extra muscles from lack of myostatin, too.

An unusual opportunity to examine myostatin’s role in humans arose when Schuelke examined a newborn baby boy, almost five years ago, and was struck by the visible muscles on the infant’s upper legs and upper arms. When ultrasound proved that the muscles were roughly twice as large as other infants’, but otherwise normal, Schuelke realized that a naturally occurring mutation in the child’s myostatin gene might be the cause.

Sequencing the myostatin gene from the boy and his mother, who had been a professional athlete, revealed a single change in the building blocks of the gene’s DNA. Surprisingly, the change was not in the gene regions that correspond to the resulting protein, but in the intervening regions that are used only to create protein-making instructions, thus changing the gene’s protein-building message.

“The mutation caused the gene’s message, the messenger RNA, to be wrong,” says Hopkins

neurologist Kathryn Wagner, M.D., Ph.D., who tested the genetic mutation’s effect in laboratory studies. “If the message had been used to make a protein, it would be much shorter than it should be. But we think the process doesn’t even get that far; instead the cells just destroy the message.”

Co-authors from Wyeth Research, Cambridge, Mass., analyzed samples of the child’s blood for evidence of the myostatin protein and found none. “Both copies of the child’s myostatin gene have this mutation, so little if any of the myostatin protein is made,” says Schuelke. “As a result, he has about twice the muscle mass of other children.”

Completely lacking myostatin, the boy is stronger than other children his age, and fortunately has no signs of problems with his heart so far, Schuelke says. But he adds that it’s impossible to know whether the lack of myostatin in that crucial muscle might lead to problems as the boy gets older.

While other family members — the boy’s mother and her brother, father and grandfather — were also reported to have been usually strong, only the mother’s DNA was available for analysis along with her son’s. Schuelke discovered that only one copy of the mother’s myostatin gene had the mutation found in both copies of her son’s myostatin gene. (We have two copies of each gene; one inherited from the mother and one inherited from the father.)

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Article adapted by MD Sports Weblog from original press release.
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 Contact: Joanna Downer
Johns Hopkins Medical Institutions

 

The Johns Hopkins researchers were funded by the National Institutes of Health and the Muscular Dystrophy Association. The German researchers were funded by the parents’ self-help group (Helft dem muskelkranken Kind).

Authors on the paper are Schuekle, Christoph Hubner, Thomas Riebel and Wolfgang Komen of Charite, University Medical Center Berlin, Germany; Wagner and Lee of Johns Hopkins; Leslie Stolz and James Tobin of Wyeth Research, Cambridge, Ma.; and Thomas Braun of Martin-Luther-University, Halle-Wittenberg, Germany.

*Under a licensing agreement between MetaMorphix Inc. and The Johns Hopkins University, Lee is entitled to a share of royalty received by the University on sales of products described in this article. Lee also is entitled to a share of sublicensing income from arrangements between MetaMorphix and American Home Products (Wyeth Ayerst Laboratories) and Cape Aquaculture Technologies. Lee and the University own MetaMorphix Inc. stock, which is subject to certain restrictions under University policy. Lee owns Cape Aquaculture Technologies stock, which is subject to certain restrictions under University policy. Lee has served as a paid consultant to MetaMorphix Inc. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

And it increases endurance to run a mile and decreases inflammation

The Salk Institute scientist who earlier discovered that enhancing the function of a single protein produced a mouse with an innate resistance to weight gain and the ability to run a mile without stopping has found new evidence that this protein and a related protein play central roles in the body’s complex journey to obesity and offer a new and specific metabolic approach to the treatment of obesity related disease such as Syndrome X (insulin resistance, hyperlipidemia and atherosclerosis).

Dr. Ronald M. Evans, a Howard Hughes Medical Investigator at The Salk Institute’s Gene Expression Laboratory, presented two new studies (date) at Experimental Biology 2005 in the scientific sessions of the American Society for Biochemistry and Molecular Biology. The studies focus on genes for two of the nuclear hormone receptors that control broad aspects of body physiology, including serving as molecular sensors for numerous fat soluble hormones, Vitamins A and D, and dietary lipids.

The first study focuses on the gene for PPARd, a master regulator that controls the ability of cells to burn fat. When the “delta switch” is turned on in adipose tissue, local metabolism is activated resulting in increased calorie burning. Increasing PPARd activity in muscle produces the “marathon mouse,” characterized by super-ability for long distance running. Marathon mice contain altered muscle composition, which doubles its physical endurance, enabling it to run an hour longer than a normal mouse. Marathon mice contain increased levels of slow twitch (type I) muscle fiber, which confers innate resistance to weight gain, even in the absence of exercise.

Additional work to be reported at Experimental Biology looks at another characteristic of PPARd: its role as a major regulator of inflammation. Coronary artery lesions or atherosclerosis are thought to be sites of inflammation. Dr. Evans found that activation of PPARd suppresses the inflammatory response in the artery, dramatically slowing down lesion progression. Combining the results of this new study with the original “marathon mouse” findings suggests that PPARd drugs could be effective in controlling atherosclerosis by limiting inflammation and at the same time promoting improved physical performance.

Dr. Evans says he is very excited about the therapeutic possibilities related to activation of the PPARd gene. He believes athletes, especially marathon runners, naturally change their muscle fibers in the same way as seen in the genetically engineered mice, increasing levels of fat-burning muscle fibers and thus building a type of metabolic ‘shield” that keeps them from gaining weight even when they are not exercising.

But athletes do it through long periods of intensive training, an approach unavailable to patients whose weight or medical problems prevent them from exercise. Dr. Evans believes activating the PPARd pathway with drugs (one such experimental drug already is in development to treat people with lipid metabolism) or genetic engineering would help enhance muscle strength, combat obesity, and protect against diabetes in these patients.

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Article adapted by MD Sports Weblog from original press release.
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Contact: Sarah Goodwin
Federation of American Societies for Experimental Biology

Whippets are bred for speed and have been clocked at speeds approaching 40 miles per hour over a 200-yard racing course. Scientists at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), have now discovered a genetic mutation that helps to explain why some whippets run even faster than others. Published in the open-access journal PLoS Genetics, their findings will make for a fascinating experiment in applied genetics and human nature: what will dog breeders do with this information, and what are the implications for human athletic performance?

A research team led by Elaine Ostrander, chief of the Cancer Genetics Branch in NHGRI’s Division of Intramural Research, reports that a mutation in a gene that codes for a muscle protein known as myostatin can increase muscle mass and enhance racing performance in whippets. Like humans, dogs have two copies of every gene, one inherited from their mother and the other from their father. Dr. Ostrander and colleagues found those whippets with one mutated copy of the myostatin (MTSN) gene and one normal copy to be more muscled than normal and are among the breed’s fastest racers. However, their research also showed that whippets with two mutated copies of the MTSN gene have a gross excess of muscle and are rarely found among competitive racers.

This is the first work to link athletic performance to a mutation in the myostatin gene, with Dr. Ostrander observing: “The potential to increase an athlete’s performance by disrupting MSTN either by natural or perhaps artificial means could change the face of competitive human and canine athletics.” However, the authors stress that: “Extreme caution should be exercised when acting upon these results because we do not know the consequences for overall health associated with myostatin mutations.”

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Article adapted by MD Sports Weblog from original press release.
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Contact: Johanna Dehlinger
Public Library of Science

CITATION: Mosher DS, Quignon P, Bustamante CD, Sutter NB, Mellersh CS, et al. (2007) A Mutation in the Myostatin Gene Increases Muscle Mass and Enhances Racing Performance in Heterozygote Dogs. PLoS Genet. doi:10.1371/journal.pgen.0030079.eor
 

New research on the effects of the female sex hormone estrogen in the brain lend credence to what many women have suspected about the hormonal changes that accompany aging: Menopause can make you fat.Scientists long have sought to understand how changes in hormones during menopause could account for the increase in appetite and accompanying weight gain that often occurs among aging women.

In a series of animal experiments described today at the 234th national meeting of the American Chemical Society, the world’s largest scientific society, researchers showed how estrogen receptors located in the hypothalamus serve as a master switch to control food intake, energy expenditure and body fat distribution. When these receptors are destroyed, the animals immediately begin to eat more food, burn less energy and pack on pounds.

This research seems to support a link between estrogen and regulation of obesity, especially the dangerous accumulation of abdominal fat linked to heart disease, diabetes, and cancer, says Deborah J. Clegg, Ph. D., assistant professor of psychiatry at the University of Cincinnati Academic Health Center, who is directing the studies.

The findings may also help scientists develop more targeted hormone replacement therapies, capable of stimulating estrogen receptors in one part of the brain or body while dampening it in the next, Clegg says.

Estrogen receptors are located on cells throughout a woman’s body. Previous studies have shown that one type of estrogen receptor, known as estrogen receptor alpha or ER-alpha, plays a role in regulating food intake and energy expenditure. But scientists have been unable to pinpoint exactly where these fat-regulating receptors reside or how they work to govern these behaviors.

To determine the effect of dwindling estrogen levels in the brain, Clegg and her colleagues are focusing on two ER-alpha rich regions located in the hypothalamus, an area of the brain that controls body temperature, hunger and thirst. The first region, called the ventromedial nucleus or VMN, is a key center for energy regulation.

Using a relatively new gene-silencing technique called RNA interference, the researchers in earlier research deactivated the alpha-receptors in the VMN. The estrogen receptors in other regions of the brain maintained their normal capacity.

When estrogen levels in the VMN dipped, the animals’ metabolic rate and energy levels also plummeted. The findings show the animals quickly developed an impaired tolerance to glucose and a sizable weight gain, even when their caloric intake remained the same. What’s more, the excess weight went straight to their middle sections, creating an increase in visceral fat.

The findings suggested that the ER-alpha in this region plays an essential role in controlling energy balance, body fat distribution and normal body weight.

Clegg now plans to perform a similar experiment to deactivate ER-alpha in the arcuate nucleus region of the hypothalamus. This region contains two populations of neurons: one puts the brake on food intake and the other stimulates food intake. Clegg anticipates that a loss of estrogen in this region may create an increase in the animals’ appetites as well as their weight.

Clegg says her studies address an area that is sorely needed given the incidence and impact of gender differences in obesity and its complications.

“The accumulation of abdominal fat puts both men and women at a heightened risk of cardiovascular disease, diabetes, and insulin resistance,” she says. “Women are protected from these negative consequences as long as they carry their weight in their hips and saddlebags. But when they go through menopause and the body fat shifts to the abdomen, they have to start battling all of these medical complications.”

By identifying the critical brain regions that determine where body fat is distributed, Clegg says her findings may help scientists design hormone replacement therapies to better manage and manipulate estrogen levels.

“If we could target those critical regions and estrogen receptors associated with weight gain and energy expenditure, we could perhaps design therapies that help women sidestep many of the complications brought on by the onset of menopause,” she says.

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Article adapted by MD Sports Weblog from original press release.
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Contact: Charmayne Marsh
American Chemical Society

 The American Chemical Society — the world’s largest scientific society — is a nonprofit organization chartered by the U.S. Congress and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.

Deborah J. Clegg, Ph.D., is assistant professor of psychiatry at the University of Cincinnati Academic Health Center in Cincinnati, Ohio.

Female athletes often lose their menstrual cycle when training strenuously, but researchers have long speculated on whether this infertility was due to low body fat, low weight or exercise itself. Now, researchers have shown that the cause of athletic amenorrhea is more likely a negative energy balance caused by increasing exercise without increasing food intake.”A growing proportion of women are susceptible to losing their menstrual cycle when exercising strenuously,” says Dr. Nancy I. Williams, assistant professor of kineseology and physiology at Penn State. “If women go six to 12 months without having a menstrual cycle, they could show bone loss. Bone densities in some long distance runners who have gone for a prolonged time period without having normal menstrual cycles can be very low.”

In studies done with monkeys, which show menstrual cyclicity much like women, researchers showed that low energy availability associated with strenuous exercise training plays an important role in causing exercise-induced amenorrhea. These researchers, working at the University of Pittsburgh, published findings in the Journal of Clinical Endocrinology and Metabolism showing that exercise-induced amenorrhea was reversible in the monkeys by increasing food intake while the monkeys still exercised.

Williams worked with Judy L. Cameron, associate professor of psychiatry and cell biology and physiology at the University of Pittsburgh. Dana L. Helmreich and David B. Parfitt, then graduate students, and Anne Caston-Balderrama, at that time a post-doctoral fellow at the University of Pittsburgh, were also part of the research team. The researchers decided to look at an animal model to understand the causes of exercise-induced amenorrhea because it is difficult to closely control factors, such as eating habits and exercise, when studying humans. They chose cynomolgus monkeys because, like humans, they have a menstrual cycle of 28 days, ovulate in mid-cycle and show monthly periods of menses.

“It is difficult to obtain rigorous control in human studies, short of locking people up,” says Williams.

Previous cross-sectional studies and short-term studies in humans had shown a correlation between changes in energy availability and changes in the menstrual cycle, but those studies were not definitive.

There was also some indication that metabolic states experienced by strenuously exercising women were similar to those in chronically calorie restricted people. However, whether the increased energy utilization which occurs with exercise or some other effect of exercise caused exercise-induced reproductive dysfunction was unknown.

“The idea that exercise or something about exercise is harmful to females was not definitively ruled out,” says Williams. “That exercise itself is harmful would be a dangerous message to put out there. We needed to look at what it was about exercise that caused amenorrhea, what it was that suppresses ovulation. To do that, we needed a carefully controlled study.”

After the researchers monitored normal menstrual cycles in eight monkeys for a few months, they trained the monkeys to run on treadmills, slowly increasing their daily training schedule to about six miles per day. Throughout the training period the amount of food provided remained the standard amount for a normal 4.5 to 7.5 pound monkey, although the researchers note that some monkeys did not finish all of their food all of the time.

The researchers found that during the study “there were no significant changes in body weight or caloric intake over the course of training and the development of amenorrhea.” While body weight did not change, there were indications of an adaptation in energy expenditure. That is, the monkeys’ metabolic hormones also changed, with a 20 percent drop in circulating thyroid hormone, suggesting that the suppression of ovulation is more closely related to negative energy balance than to a decrease in body weight.

To seal the conclusion that a negative energy balance was the key to exercise-induced amenorrhea, the researchers took four of the previous eight monkeys and, while keeping them on the same exercise program, provided them with more food than they were used to. All the monkeys eventually resumed normal menstrual cycles. However, those monkeys who increased their food consumption most rapidly and consumed the most additional food, resumed ovulation within as little as 12 to 16 days while those who increased their caloric intake more slowly, took almost two months to resume ovulation.

Williams is now conducting studies on women who agree to exercise and eat according to a prescribed regimen for four to six months. She is concerned because recreational exercisers have the first signs of ovulatory suppression and may easily be thrust into amenorrhea if energy availability declines. Many women that exercise also restrict their calories, consciously or unconsciously.

“Our goal is to test whether practical guidelines can be developed regarding the optimal balance between calories of food taken in and calories expended through exercise in order to maintain ovulation and regular menstrual cycles,” says Williams. “This would then ensure that estrogen levels were also maintained at healthy levels. This is important because estrogen is a key hormone in the body for many physiological systems, influencing bone strength and cardiovascular health, not just reproduction.”

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Article adapted by MD Sports Weblog from original press release.
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Contact: A’ndrea Elyse Messer
Penn State