Category: Uncategorized

HIV Non-disclosure, Stigma, Incarceration Are Possible Predictors of Poor Follow Up in Research Trials

July 22nd, 2014 in Uncategorized

A collaborative effort between American, Russian and Ukrainian researchers offers new insight into a well-known barrier to high quality, longitudinal HIV research: loss of participant follow up.  This study, led by researchers at the BU Schools of Medicine and Public Health, explored the factors that contributed to attrition in large HIV trial in Russia, a country in which increasing amounts of HIV-related research is being conducted. Their results were published in the June 2014 issue of HIV Clinical Trials.

Any research study that experiences significant loss of participants is at risk for bias: the possibility the missing individuals were not lost randomly.  For example, a medication trial of a 100 people, in which 30 people cannot follow up because they are hospitalized due to severe side effects, will look artificially positive if outcomes data are based on the remaining 70 individuals. Accordingly, the quality of a study will suffer and its findings may be called into question.

This is a particular problem in Russia, as injection drug use (IDU) represents a relatively higher cause of HIV transmission, which has in some studies been associated with factors that negatively impact follow-up: younger age, depression, mental illness, and concomitant alcohol use. However, this has not been a consistent finding, and other relevant factors like HIV non-disclosure status, perceived HIV stigma, and incarceration history have not been thoroughly explored until now.

Tetiana Kiriazova

Tetiana Kiriazova

The researchers analyzed the data from the HIV’s Evolution in Russia – Mitigating Infection Transmission and Alcoholism in a Growing Epidemic (HERMITAGE) study, in which patients were asked to return for six and 12 month assessments.  Of the 660 participants in the study surviving until follow-up, 168 (25.5 percent) did not return for their 12 month follow up visit, and 101 (15.3 percent) never attended any follow-up visit at all, despite extensive retention strategies. Their analysis revealed that participants with current IDU and HIV status non-disclosure missed their first study at approximately 40 percent higher rates than those who did not. They also observed binge drinking was more likely to affect loss to follow up in men than in women, that that a history of incarceration was a stronger predictor of the same in women than in men.

BUSM Postdoctoral Fellow Tetiana Kiriazova, a Ukranian National Institute on Drug Abuse (NIDA) Invest research fellow at the BMC Clinical Addiction Research and Education (CARE) Unit in the department of medicine, and lead author on this study, concluded that “understanding and addressing potential predictor of attrition may improve participant retention in longitudinal clinical research studies of HIV-infected persons, particularly in important but resource-limited research settings.”

Submitted by Ravi Pandit, MD, MPH

 

Transparency Lacking in Clinical Trials, BU Study Finds

July 15th, 2014 in Uncategorized

A significant percentage of completed drug clinical trials, especially those funded by industry, are not disclosed to the public, years after being completed—a trend that “threatens the validity of the clinical research literature in the U.S.,” according to a study led by a Boston University School of Public Health (BUSPH) researcher.

The study, published in the journal PLOS ONE, found that close to 30 percent of 400 randomly selected clinical trials completed in 2008 had not resulted, four years later, in either publication in a journal or the posting of results to the ClinicalTrials.gov (CTG) web site.

Studies that were funded solely by industry, or that involved smaller sample sizes, were less likely to be published, the research shows.

The study’s lead author, Dr. Christopher Gill, director of BUSPH’s Pharmaceuticals Program and an associate professor of global health, said the review raises ethical, as well as scientific, problems.

“Individuals who volunteer for clinical trials often do so out of a sense of altruism,” said Gill, a researcher with BU’s Center for Global Health and Development. ”I can imagine that many would be dismayed to learn that the results of a study that they participated in, that they took physical risks for, might never generate results known beyond the company that sponsored the trial.

“Science learns from mistakes, as well as successes,” he said. “If we only learn about the scientific success stories, we are really only seeing part of the picture.”

Gill and a former student, Hiroki Saito, found that 118 of the 400 clinical trials did not result in publication within four years of completion. The median length of time from completion to public disclosure was 602 days.

Among industry-funded studies, rates of posting to the CTG site were high for phase 3 or 4 studies, but extremely low for phase 2 studies.

“As an overall synthesis, these findings provide strong evidence of reporting bias,” Gill and Saito wrote. They said the associations between publication or posting rates and funding sources “merit further consideration, and may reflect differing motivations” among researchers.

Among academics working under a “publish or perish” model, and who represent the majority of non-industry funded studies, the study phase “may be less critical than the need to publish research findings in journals,” Gill and Saito said. By contrast, the pharmaceutical industry may publish more results for products that have advanced to phase 3 or beyond and are perceived to be commercially viable.

Gill and Saito suggested that regulatory requirements could be driving the differences in rates of posting results to the CTG. Among industry-funded, phase 3 or 4 studies, the majority of researchers posted their results at about one year from completion – coinciding closely with a one-year deadline established in 2007 by the Food and Drug Administration Amendments Act (FDAAA).

Regardless of the reasons, Gill and Saito said, transparency in clinical trials is “an essential public health good. The public must be informed if the premise of a clinical trial was confirmed or invalidated, and expects that, once a study involving human subjects is completed, its results will be published in the medical literature or posted to some other open-access platform.”

They said that in order to maintain the public’s faith in clinical research, and to protect the fidelity of the scientific literature, “it is essential that the research community unite around the common goal of maximizing transparency. “

In 2012, Gill reported that among US-based, industry-funded phase 2 or higher clinical studies, less than 25 percent had posted their results to CTG within a year of completion. Another study found that, among National Institutes of Health-funded trials, 32 percent remained unpublished after the median follow-up of 51 months from completion.

Emergency Responders More Comfortable in Active Shooting Scenarios After Training

July 11th, 2014 in Uncategorized

Emergency Medical Services vehicle (Courtesy Flickr user rolesnevich)

Emergency Medical Services vehicle (Courtesy Flickr user rolesnevich)

Emergency Medical Service (EMS) responders felt better prepared to respond to an active shooter incident after receiving focused tactical training according to a new study in the journal Prehospital and Disaster Medicine. This is the first study to specifically examine the EMS provider comfort level with respect to entering a scene where a shooter has not yet been neutralized or working with law enforcement personnel during that response.

Incidents such as the Columbine High School shooting, the Virginia Tech campus shooting, the 2009 Fort Hood shooting, the movie theater shooting in Aurora, Colorado, and more recently, the Sandy Hook elementary school shooting remind us of the relative frequency of these events compared to most other mass casualty incidents for which EMS trains and prepares.

For this study, EMS providers responded to an anonymous survey both before and after a four-hour training session on joint EMS/police active shooter rescue team response. Survey questions focused on individual provider comfort level when responding to active shooter incidents compared to conventional HAZMAT incidents; comfort with providing medical care in an active shooter environment; perception of EMS provider role in an active shooter incident; and the appropriate timing of EMS response at the scene.

The survey results showed that more participants felt adequately trained to respond to an active shooter incident after focused training (87 percent) compared to before the training (36 percent) regardless of a providers prior tactical experience. Additionally, more EMS providers felt more comfortable working jointly on rescue operations with law enforcement personnel in response to an active shooter incident after training participation (93 percent) compared to before the training (61 percent).

According to the researchers, despite rapid deployment of law enforcement to neutralize an active shooter, it is not uncommon for a significant amount of time to pass before law enforcement has rendered the scene “safe.” “Unfortunately this unintentionally prolongs the time before victims can receive life-saving care on the scene, as well as at a definitive care facility,” explained lead author Jerrilyn Jones, MD, a clinical instructor of emergency medicine at Boston University School of Medicine and EMS Fellow at Boston EMS. “Our study showed that after receiving appropriate training, EMS providers felt better equipped to work on joint rescue operations even if an active shooter was still present,” added Jones, who also is an emergency room physician at Boston Medical Center.

The researchers recommend further studies be undertaken to determine the significance of such training as well as the mortality impact on patient outcomes.

To read the full study: Emergency Medical Services Response to Active Shooter Incidents: Provider Comfort Level and Attitudes Before and After Participation in a Focused Response Training Program

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BUSM MD/PhD Candidate Tracks Osteoarthritis With Nanoparticles

July 11th, 2014 in Uncategorized

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The new osteoarthritis diagnostic method exploits tantalum oxide nanoparticles as contrast agents to image surface and interior regions of cartilage coating the joints.

A chronic disease afflicting more than 27 million Americans and 630 million worldwide, osteoarthritis occurs as the protective cartilage coating on joints in the knees, hips and other parts of the body degrades. No cure for osteoarthritis exists, but treatments can slow its progression, reduce pain and restore joint functioning. Now a team of researchers led by Professor Mark Grinstaff (BME, Chemistry, MSE) has developed a sensitive imaging method that promises to enhance diagnosis of osteoarthritis and enable improved care through earlier detection and more targeted treatments.

The method combines nanotechnology, engineering and medicine, and exploits new, biocompatible nanoparticles as contrast agents to image surface and interior regions of articular cartilage (the smooth, water-rich tissue that lines the ends of bones in load-bearing joints) — regions that traditional X-ray illumination cannot detect. The research, which was funded by the National Institutes of Health, is described in the June 30 issue of Angewandte Chemie.

“In the short term, these contrast agents could be used to image cartilage over time to monitor the efficacy of proposed osteoarthritis drugs,” said Grinstaff. “With continued development, they may enable clinicians to diagnose and stage the disease so that the most appropriate course of treatment could be followed.”

Two members of Grinstaff’s lab, MD/PhD student Jonathan Freedman (Pharmacology) and Postdoctoral Fellow Hrvoje Lusic (BME and Chemistry), synthesized a new nanoparticle contrast agent made of tantalum oxide that diffuses into the cartilage, thus enabling clinicians to use CT-scans to assess cartilage thickness and pinpoint lesions and injuries in osteoarthritic tissue. Guided by their clinical collaborator, Beth Israel Deaconess Medical Center/Harvard Medical School physician Brian Snyder, Freedman and Lusic used the nanoparticles to successfully image rat articular cartilage in in vivo and ex vivo experiments, as well as in a cadaverous finger joint.

They chose tantalum as a contrast agent material because it absorbs a greater fraction of X-rays produced at clinical scanning voltages than traditional materials. In addition, the tantalum nanoparticles’ positive charge automatically directs the particles to the cartilage, which carries a negative charge. Building on their initial success, the researchers plan to conduct additional in vivo experiments in animal models.

The impetus for exploring new and better contrast agents came from Snyder, who sought better ways to diagnose and assess treatment of osteoarthritis. Grinstaff sees the new method as especially promising for early detection of the disease.

“Today we have very poor capability to detect early stage osteoarthritis,” said Grinstaff. “Most patients come into the clinic at stage three when the pain becomes significant, but if diagnostics based on our method is done proactively, many patients could get the treatment they need much earlier and avoid a lot of discomfort.”

Submitted by Mark Dwortzan

BU Researchers Relate Arrests with HIV Risk Environment

July 9th, 2014 in Uncategorized

Practices used in policing injection drug users in Russia might contribute to HIV transmission and overdose mortality.

A study, conducted by researchers from Boston University Schools of Medicine and Public Health, in collaboration with St. Petersburg Pavlov State University, sought to discover the effect police arrests had on the health outcomes of a cohort of HIV-positive people with lifetime of injection drug use.

Those who were arrested by police were more likely to share needles—increasing HIV transmission—and to overdose, according to the study published in the Journal of the International AIDS Society. Their research also found no indication that police arrests reduce drug use.

“We already know that addressing individual risk behaviors is important in reducing HIV transmission among people who use drugs, who are most at risk for HIV infection,” said lead author Karsten Lunze, MD, MPH, DrPH, a BUSM assistant professor of medicine. “Our study adds that drug laws and policies, and the way they are enforced, are also important to prevent the spread of HIV.”

By linking the impact of police tactics with health outcomes of injection drug users, the researchers identified the need to create prevention programs for modifying individual behaviors and to address policing practices as part of the HIV risk environment.

“Instead of arresting people who use drugs, there should be more of a focus on facilitating access to treatment,” said Jeffrey Samet, MD, MA, MPH, a professor of medicine and community health sciences at BUSM and BUSPH who also led the study. “Public health and public safety working together can help address the increasing problem of HIV among people who use drugs.”

Further research needs to relate these findings to the operational environment of law enforcement and to understand how police interventions among injection drug users can improve, rather than worsen, the HIV risk environment, the researchers said.

The full text of the study: Punitive policing and associated substance use risks among HIV-positive people in Russia who inject drugs.

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BU Researchers and Collaborators Receive $12.6 Million NIH Grant to Study Genetics of Alzheimer’s Disease

July 7th, 2014 in Uncategorized

Researchers from the Biomedical Genetics division of the Boston University School of Medicine (BUSM) are part of a five-university collaboration receiving a $12.6 million, four-year grant from the National Institute on Aging (NIA), part of the National Institutes of Health (NIH), to identify rare genetic variants that may either protect against, or contribute to Alzheimer’s disease risk.

Lindsey Farrer

Lindsey Farrer

At BUSM, the Consortium for Alzheimer’s Sequence Analysis (CASA) is led by Lindsay A. Farrer, PhD, Chief of Biomedical Genetics and professor of medicine, neurology, ophthalmology, epidemiology, and biostatistics, who is the principal investigator. Other Boston University investigators include Kathryn Lunetta, PhD, professor of biostatistics; Gyungah Jun, PhD, assistant professor of medicine, ophthalmology and biostatistics; and Richard Sherva, PhD, research assistant professor of medicine.

CASA investigators will analyze whole exome and whole genome sequence data generated during the first phase of the NIH Alzheimer’s Disease Sequencing Program, an innovative collaboration that began in 2012 between NIA and the National Human Genome Research Institute (NHGRI), also part of NIH. They will analyze data from 6,000 volunteers with Alzheimer’s disease and 5,000 older individuals who do not have the disease. In addition, they will study genomic data from 111 large families with multiple members who have Alzheimer’s disease, mostly of Caucasian and Caribbean Hispanic descent to identify rare genetic variants.

“This is an exciting opportunity to apply new genomic technologies and computational methods to improve our understanding of the biological pathways underlying this disease,” said Farrer. “The genes and pathways we identify as integral to the Alzheimer process may become novel therapeutic targets,” he added.

Alzheimer’s disease, a progressive neurodegenerative disorder, has become an epidemic that currently affects as many as five million people age 65 and older in the United States, with economic costs that are comparable to, if not greater than, caring for those of heart disease or cancer. Available drugs only marginally affect disease severity and progression. While there is no way to prevent this disease, the discovery of genetic risk factors for Alzheimer’s is bringing researchers closer to learning how the genes work together and may help identify the most effective interventions.

This effort is critical to accomplishing the genetic research goals outlined in the National Plan to Address Alzheimer’s Disease, first announced by the U.S. Department of Health and Human Services in May 2012 and updated annually. Developed under the National Alzheimer’s Project Act, the plan provides a framework for a coordinated and concentrated effort in research, care, and services for Alzheimer’s and related dementias. Its primary research goal is to prevent and effectively treat Alzheimer’s disease by 2025.

With the current award, CASA joins the NHGRI Large-Scale Sequencing and Analysis Centers program, an NIH-supported consortium that provides large-scale sequence datasets and analysis to the biomedical community. CASA researchers will facilitate the analyses of all Alzheimer’s Disease Sequencing Project (ADSP) and additional non-ADSP sequence data to detect protective and risk variants for Alzheimer’s disease.

“We are delighted to support the important research being accomplished under this broad-based, collaborative effort. A team effort is vital to advancing a deeper understanding of the genetic variants involved in this complex and devastating disease and to the shared goal of finding targets for effective interventions,” said NIH Director Francis Collins, MD, PhD.

“Alzheimer’s disease research is appropriately one of our highest priorities,” said BUSM Dean Karen Antman, MD “We need more to better understand the genetic and environmental mechanisms that will come in part from CASA to develop more effective treatments or even better, to prevent the disease,” she added.

CASA is a collaboration of Boston University School of Medicine and four other American universities. Jonathan Haines, PhD, will lead the project at Case Western Reserve University; Richard Mayeux, MD, at Columbia University; Margaret Pericak-Vance, PhD, at the University of Miami; Gerard D. Schellenberg, PhD, at the University of Pennsylvania; and Lindsay Farrar, PhD, at Boston University.

This research is supported by the NIA grant UF1-AG047133.

Dental and Medical Students Team Up to Improve Health in East Boston

July 3rd, 2014 in Uncategorized

David Garazi DMD 15 gives an oral health screening to a child as Rifat Malhotra AS 15 records the results

David Garazi DMD 15 gives an oral health screening to a child as Rifat Malhotra AS 15 records the results

Fifteen volunteers from the BU Henry M. Goldman School of Dental Medicine (GSDM) joined together with twelve volunteers from BU School of Medicine (BUSM) to provide health care services to children and their families at the second annual Interprofessional Spring Wellness Fair at the East Boston YMCA for Healthy Kids Day last April 26.

Oral Health Promotion Kathy Lituri and Farhan Khan AS 15 organized GSDM participation in the wellness fair. The GSDM faculty sponsors were Drs. Ana Keohane and Gladys Carrasco. The GSDM student volunteers were: William Alvarez (pre-dental), Michelle DaRocha DMD 15, David Garazi DMD 15, Siavash Golaby Sanajany DMD 15, Farhan Khan AS 15, Jeongyun Kim AS 15, Andrea Lugo (pre-dental), Reefat Malhotra AS 15, Ashish Papneja DMD 15, Abdul Rahman Addas AS 14, Richa Rashmi AS 15, Neeha Sood AS 15, and Bernadette Therriault AS 15. Dr. Suzanne Sarfaty served as the BUSM faculty liaison and Samih Nassif MED 17 was team leader for the medical students.

Despite a rainy day, volunteers were in high spirits and worked efficiently. The GSDM students promoted oral health by offering oral screenings as well as information on oral health topics, such as good oral hygiene practices, healthy eating, prevention of cavities and gum disease, dry mouth, denture care, smoking cessation, and the prevention of oral cancer. GSDM had five tables set up. They provided 26 screenings to children and adults.

The BUSM students offered screenings for blood glucose levels, blood pressure, and cholesterol and measured body mass index. They also provided individualized nutrition information.

Co-organizer Farhan Khan said, “In exchange for a Saturday morning, we believe that we were able to raise awareness and help those individuals make positive health and wellness choices.” Khan continued, “Moreover, we had an excellent opportunity to be active and responsible members in our neighboring community.”

Khan noted that, in addition to giving back to the community, a secondary focus of the wellness fair was to strengthen inter-professional communication between medical and dental students. Their aim is to build a foundation of collaboration, which will be essential in a future of team-based and patient-centered health care.

Dean Jeffrey W. Hutter said, “I am very pleased to see members of the Henry M. Goldman School of Dental Medicine and School of Medicine community joining together for a common cause.” He continued, “Thank you to the volunteers who contributed to the success of this community outreach event.”

Photos are available on Facebook and Flickr.

Adults with Psychiatric Disabilities Benefit from GSDM Outreach

June 30th, 2014 in Uncategorized

Adults with Psychiatric Disabilities Benefit from GSDM Outreach

(l-r) Olga Spival (pre-dental), Marium Qureshi AS 15, and Sai Ramani Krishna Kumar AS 15

Earlier this year, volunteers from BU’s Henry M. Goldman School of Dental Medicine (GSDM) provided services to adults with psychiatric disabilities at the Center Club Boston, a program of Bay Cove Human Services. Led by Oral Health Promotion Director Kathy Lituri and in collaboration with the GSDM student chapter of the American Association of Public Health Dentistry (AAPHD), Sai Ramani Krishna Kumar AS 15, Marium Qureshi AS 15, and Olga Spival (pre-dental) participated in a wellness fair held at the club.

Center Club is a five-day-a-week program for people with psychiatric disabilities. The program combines employment, housing, and education services with social activities, wellness initiatives, and advocacy using a holistic approach and principles of self-help, peer support and empowerment.

The aim of the wellness fair was to increase health awareness through education and prevention. Approximately 250 clients and staff of Bay Cove Human Services attended. Attendees were offered basic health screenings, blood pressure and glucose checks, as well as a variety of informational activities designed to raise awareness of the many health-related programs, services, and providers located in the surrounding community. The GSDM volunteers offered oral health screenings, referrals, and education.

Said Kathy Lituri, “This was an excellent opportunity for students to participate in a community-based event, share their expertise as oral health professionals, and to learn more about the oral health issues that affect adults and their families who live with mental illness, addiction disorders, or developmental disabilities.”

Submitted by GSDM Communications.

Reproduction Later in Life is a Marker for Longevity in Women

June 26th, 2014 in Uncategorized

Women who are able to naturally have children later in life tend to live longer and the genetic variants that allow them to do so might also facilitate exceptionally long life spans.

A Boston University School of Medicine (BUSM) study published in Menopause: The Journal of the North American Menopause Society, says women who are able to have children after the age of 33 have a greater chance of living longer than women who had their last child before the age of 30.

“Of course this does not mean women should wait to have children at older ages in order to improve their own chances of living longer,” explained corresponding author Thomas Perls, MD, MPH. “The age at last childbirth can be a rate of aging indicator. The natural ability to have a child at an older age likely indicates that a woman’s reproductive system is aging slowly, and therefore so is the rest of her body.”

The study was based on analysis of data from the Long Life Family Study (LLFS)—a biopsychosocial and genetic study of 551 families with many members living to exceptionally old ages. Boston Medical Center, the teaching hospital affiliate of BUSM, is one of four study centers that make up the LLFS. The study investigators determined the ages at which 462 women had their last child and how old those women lived to be. The research found that women who had their last child after the age of 33 years had twice the odds of living to 95 years or older compared with women who had their last child by age 29.

The findings also indicate that women may be the driving force behind the evolution of genetic variants that slow aging and decrease risk for age-related genes, which help people live to extreme old age.

“If a woman has those variants, she is able to reproduce and bear children for a longer period of time, increasing her chances of passing down those genes to the next generation,” said Perls, the director of the New England Centenarian Study (NECS), a principal investigator of the LLFS and a professor of medicine at BUSM. “This possibility may be a clue as to why 85 percent of women live to 100 or more years while only 15 percent of men do.”

The results of this study are consistent with other findings on the relationship between maternal age at birth of last child and exceptional longevity. Previously, the NECS found that women who gave birth to a child after the age of 40 were four times more likely to live to 100 than women who had their last child at a younger age.

The results of Perls’ study show the importance of future research on the genetic influences of reproductive fitness because they may also impact a person’s rate of aging and susceptibility to age-related diseases, according to the researchers.

Also contributing to this study were researchers from Boston University School of Public Health, Mailman School of Public Health, Washington University and the University of Pennsylvania.

The Long Life Family Study is funded by the U.S. National Institute on Aging/National Institutes of Health.

The Brown Fat Death Spiral

June 26th, 2014 in Uncategorized

BU-led study explores how a good fat becomes impaired

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Kenneth Walsh, director of the Whitaker Cardiovascular Institute, is the lead author on a study that sheds light on the life and death of brown fat cells and illustrates the important role of brown fat in metabolism. Photo courtesy of Kenneth Walsh

White and brown fat are the yin and yang of metabolism. We’re all familiar with white fat, the squishy stuff that bulges around our waists after a few too many doughnuts. But brown fat is more mysterious. It’s the good twin—it burns energy, produces heat, and may hold clues to combating obesity.

A new study led by Kenneth Walsh, director of the BU School of Medicine’sWhitaker Cardiovascular Institute and a MED professor of medicine, sheds light on the life—and death—of brown fat cells and illustrates the important role that brown fat plays in metabolism.

The study, published in the May Journal of Clinical Investigation, shows that feeding mice a high-fat, high-sugar diet causes their brown fat cells to malfunction, a process that Walsh likens to a “death spiral.” While it’s long been known that humans lose brown fat as they age, the study is the first to describe exactly how brown fat cells “whiten,” effectively becoming more similar to white fat.

“The biggest driver today for cardiovascular disease is obesity and metabolic dysfunction. That’s what’s bringing people into the clinic,” says Walsh. “This study further demonstrates the complex interplay between the cardiovascular and metabolic systems.”

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Normal brown fat (left) loses mitochondria and “whitens” when obesity sets in. Slides courtesy of Kenneth Walsh

White fat looks white because it’s full of molecules called lipids, which the body uses for long-term energy storage. Brown fat has lipids, too, but it is constantly using them like fuel to stoke a fire. Brown fat looks brown because is packed with mitochondria, the tiny cellular powerhouses that burn energy to keep us warm and move our muscles. (White fat, conversely, is not very metabolically active and has fewer mitochondria.) For many years, scientists thought that brown fat existed only in small mammals like mice and in newborn human babies, who need help staying warm.

Then in 2009 scientists found that adults have brown fat, too—a few pockets in their necks and chests. Since lean people have more brown fat than obese people, the scientists suspected that brown fat might somehow play a role in gaining weight or in keeping it off.

“For years brown fat was a scientific backwater, because we thought it was only in fuzzy little animals and babies,” Walsh says. “Suddenly it became part of the adult metabolic equation. Now it’s one of the hottest topics in metabolism.”

But big questions remain: does brown fat play a significant role in adult human metabolism? Can white fat become brown? Why do we lose brown fat as we age? How exactly does brown fat whiten, and is there a way to stop it?

In the study, Walsh and his colleagues tried to tackle the last question: what is happening, on a molecular level, when brown fat turns white? To answer the question, they fed normal mice high-fat, high-sugar mouse chow—much like the average American diet—and let them eat as much as they wanted. After eight weeks, remarkable changes were apparent: the mice had gained weight (white fat, unfortunately) and become insulin-resistant—a precursor to diabetes. And their brown fat, no longer able to burn energy efficiently, had become engorged with lipids. In effect, the brown fat had begun to turn white.

“You take a normal lab mouse, give it a fast-food diet full of fat and sugar, and it throws them out of whack,” says Walsh. “It totally confuses their metabolism.”

Normal brown fat (left) is fed by many blood vessels, seen here in green. In obese mice, blood vessels feeding the brown fat shriveled and disappeared. Slides courtesy of Kenneth Walsh

Normal brown fat (left) is fed by many blood vessels, seen here in green. In obese mice, blood vessels feeding the brown fat shriveled and disappeared. Slides courtesy of Kenneth Walsh

What happened? By studying tissue and blood samples from the mice at different times after starting the fast-food diet, Walsh and his colleagues teased apart the chain of events that led to the demise of brown fat. First, they discovered, the unhealthy diet led to high level of toxic fatty acids in the brown fat. This led to the malfunction of a gene called VEGFA (vascular endothelial growth factor A), which helps control the growth of blood vessels in adult tissues. Without a well-functioning VEGFA gene, blood vessels feeding the brown fat shriveled and disappeared, sharply reducing its blood supply. Deprived of blood, and thus oxygen, the mitochondria in the brown fat cells couldn’t burn lipids efficiently, so the fuel began to pile up. The result: brown fat turned white. “It was a pathological cascade, a death spiral,” Walsh says. “Metabolic dysfunction led to the loss of blood vessels, and blood vessel loss impaired brown fat, leading to more metabolic dysfunction. What was really surprising is that the white fat was minimally affected by blood vessel loss, but the brown fat disintegrated.”

Then came the rescue attempt. Walsh and his colleagues used a virus to insert the gene for VEGFA into the brown fat of obese mice. The infusion of VEGFA didn’t bring the mice back to normal, but it had a restorative effect: the mice’s blood vessels stopped withering, the brown fat perked up and improved its function, and the insulin resistance improved.

It’s too early to say whether this work may eventually lead to new treatments for obesity in humans. But it does shed light on the critical role that the growth and atrophy of blood vessels may play in the maintenance of brown fat, and it demonstrates the rapid tumble toward metabolic dysfunction and obesity once brown fat starts to fail. The new knowledge gives clues for potential targets and treatments. By some predictions, half of the American population will be obese by 2050. To reverse the obesity epidemic, we may need all the clues that science can offer.

This BU Today story was written by Barbara Moran (COM’96) is a science writer in Brookline, Mass. She can be reached through her website WrittenByBarbaraMoran.com.