Tag Archive for: Nadler

clinician measuring obese child's waist

Surgeon says treatment silos in childhood obesity need to end

clinician measuring obese child's waist

An editorial in one of the top-ranked pediatric journals — Lancet Child & Adolescent Health — asserts that researchers studying obesity in children and adolescents should stop comparing medication versus bariatric surgery to see which is more effective.

An editorial in one of the top-ranked pediatric journals — Lancet Child & Adolescent Health — asserts that researchers studying obesity in children and adolescents should stop comparing medication versus bariatric surgery to see which is more effective.

Evan Nadler, M.D., director of the Child and Adolescent Weight-loss Surgery Program at Children’s National Hospital, writes that patients don’t want or need the answer to that question. Instead, the two treatment approaches should work together. He cites the field of oncology, where medicine and surgery work hand-in-hand as a comprehensive treatment plan that is individualized for each person’s unique condition.

Why it matters

“The obesity field has long been evaluating isolated interventions. There is a battle between those who favor medical therapy and those who favor surgical therapy,” Nadler writes. “Would it not make more sense for patients if we consider all available options until the desired weight loss is achieved rather than be a staunch advocate of the therapy that we personally like the best?”

According to Nadler, the American Academy of Pediatrics’ 15-year-process to release their first guidelines for treatment of childhood obesity is a consequence of these same silos.

“If medical and surgical oncologists figured out how to work together decades ago, why is it taking so long for practitioners who treat obesity to join forces and use combination therapy for their patients?”

Read the editorial in the Lancet Child & Adolescent Health.

Evan P Nadler

Biliary complication rates similar for kids and adults after weight-loss surgery

Evan P Nadler

“We definitely need more research, across a more diverse population, to understand the mechanisms behind this higher likelihood of acute pancreatitis in pediatric patients,” says Evan Nadler, M.D., “More importantly, this study provides a proof point that weight-loss surgery doesn’t pose any higher risk of biliary complications for kids than it does for adults.”

Adolescents and teens experience biliary side effects after weight-loss surgery at about the same rate as adults. However, in younger patients, the symptoms are more likely to manifest as pancreatic inflammation, or acute pancreatitis, according to a new study published in the November issue of the journal Obesity.

“Biliary issues after laparoscopic sleeve gastrectomy occur with about the same frequency in pediatric patients as they do in adults,” says Evan Nadler, M.D., senior author on the study and director of the Bariatric Surgery Program at Children’s National Hospital. “We were surprised, however, to find that the small number of pediatric patients who do experience these complications seem to be more likely to have acute pancreatitis as a result. In adults, it’s more commonly the gall bladder that acts up as opposed to the pancreas.”

The study included 309 patients without previous or concurrent history of biliary disease or gallstones who had undergone laparoscopic sleeve gastrectomy at Children’s National. Twenty-one patients, or 6.7% of the cohort, were diagnosed with biliary disease after surgery. Sixty-two percent of the pediatric patients with biliary disease also showed signs of acute pancreatitis, while only one-third of those with post-operative biliary disease presented with a gallstone blockage, or biliary colic. In adults, biliary colic is a primary symptom after surgery and far fewer adults experience acute pancreatitis.

“We definitely need more research, across a more diverse population, to understand the mechanisms behind this higher likelihood of acute pancreatitis in pediatric patients. More importantly, this study provides a proof point that weight-loss surgery doesn’t pose any higher risk of biliary complications for kids than it does for adults.”

Obesity’s editorial team selected the study as one of the Top 5 most innovative scientific research studies to prevent and treat obesity in 2019. It appears in a special section of the November 2019 print edition. Dr. Nadler will present his findings during the Obesity Journal Symposium on Nov. 5, 2019, as part of ObesityWeek®, the annual meeting of The Obesity Society.

“We’ve got one of the largest, if not the largest, weight-loss surgery programs dedicated solely to caring for children and adolescents,” adds Dr. Nadler. “That gives us a unique ability to collect and analyze a statistically significant sample of pediatric-specific patient data and really contribute a better understanding of how bariatric surgery specifically impacts younger patients.”

In late October 2019, the American Academy of Pediatrics issued guidance with the aim of providing severely obese teens easier access to bariatric surgery.

“Our study is just the latest contribution to a significant body of evidence that weight-loss surgery should be considered a viable treatment approach for children and teenagers with severe obesity, an idea that is now endorsed by the nation’s largest organization of pediatricians,” he points out.

The Obesity Journal Symposium occurs on Tuesday, Nov. 5, 2019, from 3:30 – 5:00 p.m. at the Mandalay Bay South Convention Center in Las Vegas, Nev. ObesityWeek® is a partnership of The Obesity Society and the American Society for Metabolic and Bariatric Surgery.

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Presentation: Pattern of Biliary Disease Following Laparoscopic Sleeve Gastrectomy in Adolescents

Session: Obesity Journal Symposium

Date/Time: 11/5/2019, 3:30 pm – 5:00 pm

Co-authors: Jun Tashiro , Arunachalam A. Thenappan, and Evan P. Nadler

Julia Finkel

Two Children’s National spin-outs join Johnson & Johnson–JLABS

Julia Finkel

AlgometRx, which joins JPOD @ Philadelphia, was founded by Julia Finkel, M.D., pediatric anesthesiologist and director of Pain Medicine and Research at Children’s Sheikh Zayed Institute.

AlgometRx and Adipomics, two companies that spun out of innovations discovered at Children’s National Health System, have been selected by Johnson & Johnson Innovation – JLABS to join JPOD @ Philadelphia and JPOD @ Boston, respectively.

JLABS is a global network of no-strings-attached incubators for innovative companies from across the pharmaceutical, medical device, consumer and health technology sectors. Start-up companies are free to pursue their own research priorities independently, with access to state-of-the-art facilities to develop new drugs, medical devices, precision diagnostics and health technologies for people around the world.

Both companies got their start at the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National. The Institute focuses on research and innovation that can improve health for children everywhere.

AlgometRx, which joins JPOD @ Philadelphia, was founded by Julia Finkel, M.D., pediatric anesthesiologist and director of Pain Medicine and Research at Children’s Sheikh Zayed Institute. The AlgometRx device is a first-of-its-kind platform technology that aims to objectively measure pain intensity, type and drug effects in real time by capturing a digital image of a patient’s pupillary light response and applying a series of proprietary algorithms to various characteristics.

AlgometRx is designed to provide an objective pain measurement that aims to help physicians select the correct analgesic class of drug and dosage. By optimizing pain assessment, drug selection and drug management, AlgometRx aims to impact the opioid epidemic and the monitoring and management of Opioid Use Disorder.

Robert Freishtat and Evan Nadler

Adipomics, which joins JPOD @ Boston, was co-founded by Robert Freishtat, M.D., M.P.H., senior investigator in the Center for Genetic Medicine of the Children’s Research Institute and chief of the Division of Emergency Medicine at Children’s National, and pediatric surgeon Evan P. Nadler, M.D., co-director of the Obesity Program and director of the Bariatric Surgery Program at Children’s National.

Adipomics, which joins JPOD @ Boston, was co-founded by pediatric surgeon Evan P. Nadler, M.D., co-director of the Obesity Program and director of the Bariatric Surgery Program at Children’s National, and Robert Freishtat, M.D., M.P.H., senior investigator in the Center for Genetic Medicine of the Children’s Research Institute and chief of the Division of Emergency Medicine at Children’s National. Adipomics was founded with the aim to address the global epidemic of obesity-related diseases including Type 2 diabetes and cardiovascular diseases. World health experts predict that one billion people worldwide will be obese by 2030.

Drs. Nadler and Freishtat discovered that exosomes released from fat cells (adipocytes) carry genetic material that can mediate various diseases related to obesity. Through their research, they developed a proprietary method that aims to detect how obesity affects an individual patient’s metabolism before the onset of overt disease. Adipomics aims to create the first non-invasive, “anticipatory medicine” diagnostic that detects risk for obesity-related diseases prior to the onset of clinical signs or even biochemical abnormalities. If successful, this predictive methodology would enable treatment much earlier in the disease process, which is likely to improve effectiveness.

A recent news release from Children’s National provides more details on these innovations.

As organizations that share a commitment to improving the pace of healthcare innovation, Children’s National and Johnson & Johnson Innovation – JLABS also recently announced their collaboration to launch JLABS @ Washington, DC,  a 32,000-square foot facility to be located at the new Children’s National Research & Innovation Campus in Washington, D.C. The JLABS @ Washington, DC will have the capacity to house up to 50 pharmaceutical, medical device, consumer and health technology companies that are aiming to advance the development of new drugs, medical devices, precision diagnostics and health technologies, including applications in pediatrics. The campus is located on a 12-acre portion of the former Walter Reed Army Medical Center campus in the nation’s capital and is slated to open in 2020, coinciding with the 150th Anniversary of Children’s National Health System.

ACC19 attendees from Children's National

ACC.19: A focus on pediatric cardiology

ACC19 attendees from Children's National

Dr. Gerard Martin, center, accepts an award before delivering the 2019 Dan G. McNamara Keynote lecture at ACC.19.

“Innovation meets tradition,” is how many attendees and journalists described the American College of Cardiology’s 68th Scientific Sessions (ACC.19), which took place March 16-18, 2019 in New Orleans, La.

Gerard Martin, M.D., F.A.A.P., F.A.C.C., F.A.H.A., a pediatric cardiologist and the medical director of Global Services at Children’s National, supported this narrative by referencing both themes in his 2019 Dan G. McNamara keynote lecture, entitled “Improved Outcomes in Congenital Heart Disease through Advocacy and Collaboration.” Dr. Martin highlighted advancements in the field of pediatric cardiology that took place over the past 15 years, while touting modern advancements – such as pulse oximetry screenings for critical congenital heart disease – that were a result of physician-led advocacy and collaboration.

Dr. Martin’s message was to continue to invest in research and technology that leads to medical breakthroughs, but to remember the power of partnerships, such as those formed by the National Pediatric Cardiology Quality Improvement Collaborative. These alliances, which generated shared protocols and infrastructure among health systems, improved interstage mortality rates between surgeries for babies born with hypoplastic left heart syndrome.

A dozen cardiologists and clinicians from the Children’s National Heart Institute also participated in CME panel discussions or delivered poster presentations to support future versions of this template, touching on early-stage innovations and multi-institution research collaborations. The themes among Children’s National Heart Institute faculty, presented to a diverse crowd of 12,000-plus professional attendees representing 108 countries, included:

Personalized guidelines:

  • Sarah Clauss, M.D., F.A.C.C., a cardiologist, presented “Unique Pediatric Differences from Adult Cholesterol Guidelines: Lipids and Preventive Cardiology,” before Charles Berul, M.D., division chief of cardiology and co-director of the Children’s National Heart Institute, presented “Unique Pediatric Differences from Adult Guidelines: Arrhythmias in Adults with Congenital Heart Disease,” in a joint symposium with the American Heart Association and the American College of Cardiology.
  • Berul, who specializes in electrophysiology, co-chaired a congenital heart disease pathway session, entitled “Rhythm and Blues: Electrophysiology Progress and Controversies in Congenital Heart Disease,” featuring components of pediatric electrophysiology, including heart block, surgical treatment of arrhythmias and sudden death risk.

Early detection:

  • Anita Krishnan, M.D., associate director of the echocardiography lab, presented “Identifying Socioeconomic and Geographic Barriers to Prenatal Detection of Hypoplastic Left Heart Syndrome and Transposition of the Great Arteries” as a moderated poster in Fetal Cardiology: Quickening Discoveries.
  • Jennifer Romanowicz, M.D., a cardiology fellow, and Russell Cross, M.D., director of cardiac MRI, presented the “Neonatal Supraventricular Tachycardia as a Presentation of Critical Aortic Coarctation” poster in FIT Clinical Decision Making: Congenital Heart Disease 2.
  • Pranava Sinha, M.D., a cardiac surgeon, presented the poster “Neuroprotective Effects of Vitamin D Supplementation in Children with Cyanotic Heart Defects: Insights from a Rodent Hypoxia Model” in Congenital Heart Disease: Therapy 2.

Coordinated care:

  • Ashraf Harahsheh, M.D., F.A.C.C., F.A.A.P., a cardiologist with a focus on hyperlipidemia and preventive cardiology, co-presented an update about BMI quality improvement (Q1) activity from the American College of Cardiology’s Adult Congenital and Pediatric Quality Network – BMI Q1 leadership panel.
  • Niti Dham, M.D., director of the cardio-oncology program, and Deepa Mokshagundam, M.D., cardiology fellow, presented the poster “Cardiac Changes in Pediatric Cancer Survivors” in Heart Failure and Cardiomyopathies: Clinical 3.
  • Nancy Klein, B.S.N., R.N., C.P.N., clinical program coordinator of the Washington Adult Congenital Heart program at Children’s National, presented the poster “Improving Completion of Advanced Directives in Adults with Congenital Heart Disease” in Risks and Rewards in Adult Congenital Heart Disease.

Innovation:

  • Jai Nahar, M.D., a cardiologist, moderated “Future Hub: Augmented Cardiovascular Practitioner: Giving Doctors and Patients a New Voice.” The session focused on technical aspects of artificial intelligence, such as language processing and conversational artificial intelligence, as well as how applications are used in patient-physician interactions.
  • Nahar also participated in a key event on the Heart-to-Heart stage, entitled “Rise of Intelligent Machines: The Potential of Artificial Intelligence in Cardiovascular Care.”

“While I enjoyed the significant representation of Children’s National faculty at the meeting and all of the presentations this year, one research finding that I found particularly compelling was Dr. Krishnan’s poster about geographical disparities in detecting congenital heart disease,” says Dr. Berul. “Her research finds obstetricians providing care to women in the lowest quartile of socioeconomic areas were twice as likely to miss a diagnosis for a critical congenital heart defect during a fetal ultrasound, compared to obstetricians providing care for women in the highest quartiles.”

Dr. Krishnan’s study was the collaborative effort of 21 centers in the United States and Canada, and investigated how socioeconomic and geographic factors affect prenatal detection of hypoplastic left heart syndrome and transposition of the great arteries.

“We studied over 1,800 patients, and chose these diseases because they require early stabilization by a specialized team at a tertiary care center,” says Dr. Krishnan, who led the research in conjunction with the Fetal Heart Society Research Collaborative. “We hope that by understanding what the barriers are, we can reduce disparities in care through education and community-based outreach.”

Elizabeth Estrada

A new type 2 diabetes program leader in a time of change

Elizabeth Estrada

Elizabeth Estrada, M.D., was struck by the increasing number of children with obesity and type 2 diabetes when she finished her fellowship in 1996. That fascination, along with increasingly alarming statistics about the rise in type 2 diabetes in youth over the past 20 years, steered her to a career focused on pediatric diabetes and metabolism that eventually led her to Children’s National Health System, where she will become the director of the type 2 diabetes program this spring.

Coming most recently from the University of North Carolina, where she served as Chief of the Division of Pediatric Endocrinology and Diabetes, Dr. Estrada will work closely with Children’s National Endocrinology Division Chief Andrew Dauber, M.D., and Diabetes Services Director Fran Cogen, M.D., to create a multidisciplinary type 2 diabetes care structure that she has seen success with throughout her career.

“Children with type 2 diabetes have very different needs than children with type 1,” Dr. Estrada explains. “They need more nutrition, more social work, and psychological support.”

Children’s National presents Dr. Estrada with a unique opportunity at a time when the field of care and treatment options for children with type 2 diabetes is expanding. She aims to develop a comprehensive, multidisciplinary program integrating the established Children’s National obesity program with the nationally-ranked endocrinology and diabetes team, which has a strong foundation in providing psychological support to families, which is part of a larger toolkit at Children’s National to help families manage a diabetes diagnosis.

The obesity program at Children’s National emphasizes personalized clinical care and education to prevent and reduce the prevalence of obesity, incorporating multiple aspects of medical and surgical care for obese children and adolescents through the Improving Diet, Energy and Activity for Life (IDEAL) clinic and the bariatric surgery program. The IDEAL clinic helps children with dietary counseling, health education classes, physical activity and weight-management techniques, as well as psychosocial support to help children reach and maintain a healthy weight.

One of the first children’s hospitals to be accredited by the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP®) and the only hospital in the area to be accredited to perform bariatric surgery on adolescents, the bariatric surgery program at Children’s National is directed by Evan Nadler, M.D., who has been safely performing surgeries for nearly 15 years.

The American Diabetes Association (ADA) recently published updates to the “Standards of Medical Care in Diabetes,” which provides research-based practice recommendations for children and adolescents with type 2 diabetes, including metabolic surgery as a treatment recommendation, stating:

The results of weight-loss and lifestyle interventions for obesity in children and adolescents have been disappointing, and no effective and safe pharmacologic intervention is available or approved by the U.S. Food and Drug Administration in youth. Over the last decade, weight-loss surgery has been increasingly performed in adolescents with obesity. Small retrospective analyses and a recent prospective multicenter nonrandomized study suggest that bariatric or metabolic surgery may have benefits in obese adolescents with type 2 diabetes similar to those observed in adults.

The recommendations further stipulate that metabolic surgery should only be considered under certain circumstances, including for those adolescents with T2D who are markedly obsess (BMI > 35 kg/m2) and who have uncontrolled glycemia and/or serious comorbidities despite lifestyle and pharmacologic intervention, and it should only be performed by an experienced surgeon working as part of a well-organized and engaged multidisciplinary team.

Working closely with Dr. Nadler and the obesity team will be a hallmark of Dr. Estrada’s role.

Her goal is to organize a clinic that not only provides clinical care and surgical options, but also includes research and provides medical education and training to medical students, residents and fellows. Dr. Estrada’s own research has focused on insulin resistance, one of the underlying problems in type 2 diabetes.

“There are several clinical trials currently exploring the efficacy and safety of medications for type 2 diabetes in children, something that is incredibly important since Metformin and insulin are the only approved options at this point,” Estrada says. “It is imperative that we bring research to Children’s National as a complement to the existing programs and to continue providing the highest level of care for these patients.”

The Division of Diabetes and Endocrinology works with the National Institutes of Health, conducts independent research and received support from the Washington Nationals Dream Foundation for its diabetes program, the largest pediatric diabetes program in the region, which provides community education and counsels 1,800 pediatric patients each year.

child measuring belly with tape measure

Children’s obesity research team presents compelling new findings

child measuring belly with tape measure

Faculty from Children’s National Health System’s Department of Psychology & Behavioral Health set out to learn if any demographic, psychiatric, or cognitive factors play a role in determining if an adolescent should be eligible for bariatric surgery, and what their weight loss outcomes might be. Presenting at the Society for Pediatric Psychology Annual Conference earlier this month, a group of researchers, fellows and clinicians, including surgeons from Children’s National showcased their findings. One of the posters developed by Meredith Rose, LGSW, ML, who works as an interventionist on a Children’s National clinical research team, received special recognition in the Obesity Special Interest Group category.

One presentation reported on a total of 222 pediatric patients with severe obesity, which is defined as 120 percent of the 95th percentile for Body Mass Index. Mean age of the participants was 16 years of age, 71 percent were female and 80 percent where Hispanic or non-White. As part of their preparation for surgery, all patients were required to complete a pre-bariatric surgery psychological evaluation, including a clinical interview and Schedule for Affective Disorders and Schizophrenia (KSADS-PL) screening. The studies by the Children’s teams were based on a medical record review of the pre-screening information. Adolescents being evaluated for surgery had high rates of mental health diagnoses, particularly anxiety and depression, but also included Attention Deficit Hyperactivity Disorder, eating disorders, and intellectual disability.

Another Children’s presentation at the conference looked at weight loss outcomes for adolescents based on IQ and intellectual disability. Overall, neither Full Scale IQ from the Wechsler Abbreviated Intelligence Scale – 2nd edition, nor the presence of an intellectual disability predicted weight loss following surgery.

“The sum of our research found that kids do really well with surgery,” said Eleanor Mackey, PhD, assistant professor of psychology and behavioral health. “Adolescents, regardless of the presence of intellectual disability areas are likely to lose a significant amount of weight following surgery,” added Dr. Mackey.

“This is a particularly important fact to note because many programs and insurers restrict weight loss surgery to ‘perfect’ candidates, while these data points demonstrate that our institution does not offer or deny surgery on the basis of any cognitive characteristics,” says Evan P. Nadler, M.D., associate professor of surgery and pediatrics. “Without giving these kids a chance with surgery, we know they face a lifetime of obesity, as no other intervention has shown to work long-term in this patient population. Our research should empower psychologists and physicians to feel more confident recommending bariatric surgery for children who have exhausted all other weight loss options.”

The research team concluded that examining how individual factors, such as intellectual disability, psychiatric diagnoses, and demographic factors are associated with the surgery process is essential to ensuring adequate and empirically supported guidelines for referral for, and provision of bariatric surgery in adolescents. Next steps by the team will include looking into additional indicators of health improvement, like glucose tolerance, quality of life, or other lab values, to continue evaluating the benefits of surgery for this population.

Adolescent brain scan from obesity study

Imaging captures obesity’s impact on the adolescent brain

Adolescent brain scan from obesity study

For the first time, a team of researchers led by Chandan Vaidya, Ph.D., chair of the Department of Psychology at Georgetown University, has used functional magnetic resonance imaging (fMRI) to capture the brain function of a small population of adolescents with obesity, both before and after bariatric surgery.

Obesity affects the whole body, from more obvious physical impacts on bones and joints to more subtle, internal impacts on organs like the brain.

For the first time, a team of researchers has used functional magnetic resonance imaging (fMRI) to capture the brain function of a small population of adolescents with obesity, both before and after bariatric surgery. The goal is to better understand the neural changes that occur when an adolescent is obese, and determine the effectiveness of interventions, such as vertical sleeve gastrectomy, at improving brain function as weight is lost.

The study, published as the November Editors’ Choice in the journal Obesity, found that executive and reward-related brain functions of study participants with obesity improved following the surgical procedure and initial weight loss.

How bariatric surgery changes the teenage brain from Research Square on Vimeo.

“We’ve known for some time that severe obesity has negative consequences on some neurocognitive function areas for adults,” says Chandan Vaidya, Ph.D., chair of the Department of Psychology at Georgetown University and a senior author of the study. “But for the first time, we’ve captured fMRI evidence in young patients, and also shown that surgical intervention and the resulting weight loss can reverse some of those deficits.”

“For me, this early evidence makes a strong case that when kids are struggling with severe obesity, we need to consider surgical intervention as an option sooner in the process,” notes Evan Nadler, M.D., director of the Bariatric Surgery Program at Children’s National Health System, who also contributed to the study. “The question that remains is whether the neurocognitive function improves more if surgery, and thus weight loss, happens earlier – and is there a time factor that should help us determine when to perform a procedure that will maximize improvements?”

The preliminary study included 36 participants and was conducted using patients recruited from the Children’s National Bariatric Surgery program, one of the first children’s hospitals to achieve national accreditation by the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program.

“We asked these questions because we know that in the kids we see, their behavioral, brain, and physical health are all very closely related to one another and have an impact on each other,” adds Eleanor Mackey, Ph.D., study senior author and co-principal investigator on the National Institute of Diabetes and Digestive and Kidney Diseases grant that funded the project. “We expected that as physical health improves, we might see corresponding improvements in brain and behavior such as cognitive and school performance.”

The study also pointed out some technical and practical challenges to studying this particular young population. Anyone with a BMI greater than 50 was not able to fit within the MR bore used in the study, preventing fMRI participation by those patients.

“In addition to future studies with a larger sample size, we’d like to see if there are neuroimaging markers of plasticity differences in a population with BMI greater than 50,” says Dr. Vaidya. “Does the severity of the obesity change how quickly the brain can adapt following surgery and weight loss?”

The abstract was selected by the journal’s editors as one that provides insights into preventing and treating obesity. It was featured at the Obesity Journal Symposium during Obesity Week 2017 in Washington, D.C., as part of the Obesity Week recognition, and a digital video abstract was also released about the findings.

Fat Cells

Cellular signals may increase atherosclerosis risk

Fat Cells

Fat cells from obese patients have the ability to send signals that can accelerate biological processes leading to atherosclerosis.

Obesity has been linked to a variety of adverse health conditions, including Type 2 diabetes, cancer, heart attack and stroke – conditions that may begin as early as childhood in patients whose obesity also begins early. While this much is known, it has been unclear how extra fat mass might lead to these chronic health conditions.

New research from Children’s National Health System scientists might help answer this question. In findings presented at the 2017 annual meeting of the Pediatric Academic Societies, the research team shows that exosomes – nanosized chemical messages that cells send to each other to regulate protein production – isolated from very obese teenage patients behave very differently from those derived from lean patients and could be key players in heightening the risk of developing atherosclerosis. This hardening of the arteries can, in turn, increase the risk of heart disease and stroke in adulthood.

A research team led by Robert J. Freishtat, M.D., M.P.H., chief of emergency medicine at Children’s National, is exploring possible links between extra belly fat and obesity-related diseases, such as atherosclerosis, a buildup of plaque in arteries that can harden and restrict blood flow. More precise knowledge of the mechanisms by which obesity ratchets up heart risks holds the promise of helping the next generation of kids avoid experiencing chronic disease.

The working theory is that exosomes derived from belly fat from obese patients have the distinct ability to accelerate biological processes leading to atherosclerosis.

The research team isolated exosomes from five obese teenagers and compared them to five sex-matched lean adolescents. It turns out that exosomes derived from fat pick up their marching orders from microRNA content likely to target cholesterol efflux genes, which help reduce cholesterol buildup in cells.

The research team looked at differences in cholesterol efflux gene expression in THP-1 macrophages. Uptake of low-density lipoprotein cholesterol, “bad” cholesterol, was 92 percent higher than in those exposed to exosomes from obese patients compared with their lean counterparts. Exposure to obese exosomes also reduced cholesterol efflux.

“Atherogenic properties of fat-cell derived exosomes from obese patients differ markedly from the non-atherogenic profile of exosomes from lean patients. It is especially concerning that we see biological clues of heightened risk in teenagers, and the finding underscores how the seeds for atherosclerosis can be planted very early in life,” Dr. Freishtat says.

The presentation is the latest finding from a research team that, over years of work, is unraveling the mechanisms of cellular signaling by fat cells.  By closely examining very obese children – who have the most severe cardiometabolic disease – the team identified strong molecular signals of disease risk that they can search for in leaner patients who may be at risk for disease years from now.

“We know that morbidly obese patients have cardiovascular issues,” explains Dr. Freishtat. “An unanswered question is for patients with no clinical symptoms who are a little overweight. Can we look at them and say whether they are at risk for developing atherosclerosis, insulin resistance or Type 2 diabetes five or 10 years down the line? That’s the whole rationale for doing this work.”

The critical issue is what exosomes are up to. Dr. Freishtat says in lean people, they’re active and are very important in maintaining stable metabolism and homeostatic processes.

“When a person becomes obese, however, exosomes evolve,” he says. “They no longer support insulin signaling, which is helpful, and drive processes in the reverse direction, repressing insulin signaling – which can be harmful,” he adds.

Ultimately, the research team aims to revolutionize how chronic diseases like Type 2 diabetes are diagnosed. For far too long, clinicians have relied on symptoms like high glucose levels and excess urination to diagnose diabetes.

“By the time you have symptoms, it’s too late,” says Dr. Freishtat. “In many cases, damage has been done by relentless exposure to high sugar levels. The biological processes that underlie the Type 2 diabetes process began five, 10, 15 years earlier. If we can detect it earlier, before symptoms arise, intervention is going to have a more significant impact on improving and extending patients’ lives.”

Scientist with centrifuge

Giving fat cell messages a positive spin

Woman on a scale

Study findings offer hope to the nearly 2 billion adults who are overweight or obese worldwide that detrimental effects of carrying too much weight can recede. (Image source: Centers for Disease Control and Prevention)

Losing weight appears to reset the chemical messages that fat cells send to other parts of the body that otherwise would encourage the development of Type 2 diabetes, substantially reducing the risk of that disease, a team led by Children’s National Health System researchers report in a new study. The findings offer hope to the nearly 2 billion adults who are overweight or obese worldwide that many of the detrimental effects of carrying too much weight can recede, even on the molecular level, once they lose weight.

In 2015, Robert J. Freishtat, M.D., M.P.H., Chief of Emergency Medicine at Children’s National and Associate Professor of Pediatrics, Emergency Medicine and Integrative Systems Biology at The George Washington University School of Medicine & Health Sciences, and colleagues showed that fat cells (also known as adipocytes) from people who are obese send messages to other cells that worsen metabolic function. These messages are in the form of exosomes, nanosized blobs whose contents regulate which proteins are produced by genes. Exosomes are like “biological tweets,” Dr. Freishtat explains — short signals designed to travel long distances throughout the body.

Dr. Freishtat’s earlier research showed that the messages contained in exosomes from patients who are obese alter how the body processes insulin, setting the stage for Type 2 diabetes. However, says Dr. Freishtat, it has remained unclear since that publication whether these aberrant messages from adipocytes improve after weight loss.

“We’ve known for a long time that too much adipose tissue is bad for you, but it’s all moot if you lose the weight and it’s still bad for you,” he explains. “We wanted to know whether these negative changes are reversible. If you reduce fat, does the disease risk that goes along with excess fat also go away?”

Details of the study

To investigate this question, Dr. Freishtat and colleagues worked with six African American adults scheduled to receive gastric bypass surgery — a nearly surefire way to quickly lose a large amount of weight. The volunteers, whose average age was 38 years, started out with an average body mass index (BMI) of 51.2 kg/m2. (The Centers for Disease Control and Prevention considers a healthy BMI to range between 18.5 to 24.9.)

Two weeks before these volunteers underwent surgery, researchers collected blood samples and took a variety of measurements. The researchers then performed a repeat blood draw and measurements one year after the surgery took place, when the volunteers’ average BMI had dropped to 32.6.

Dr. Freishtat and colleagues drew out the adipocyte-derived exosomes from both sets of blood samples and analyzed their contents. The team reports in the January 2017 issue of Obesity that at least 168 microRNAs — the molecules responsible for sending specific messages — had changed before and after surgery. Further analyses showed that many of these microRNAs were involved in insulin signaling, the pathways that the body uses to regulate blood sugar. By changing these outgoing microRNAs for the better, Dr. Freishtat says, adipocytes actively were encouraging higher insulin sensitivity in other cells, warding off Type 2 diabetes.

Sure enough, each volunteer had better insulin sensitivity and other improved markers of metabolic health post-surgery, including lower branched chain amino acids and a two-fold reduction in their glutamate to glutamine ratio.

“These volunteers were essentially cured of their diabetes after surgery. The changes we saw in their surgery-responsive microRNAS correlated with the changes we saw in their metabolic health,” Dr. Freishtat says.

A glimpse into the future

Dr. Freishtat and colleagues plan to study this phenomenon in other types of weight loss, including the slower and steadier paths that most individuals take, such as improving diet and doing more exercise. The team expects to see similar changes in exosomes of patients who lose weight in non-surgical ways.

By further examining the aberrant messages in microRNAs being sent out from adipocytes, he says, researchers eventually might be able to develop treatments to reverse metabolic problems in overweight and obese patients before they lose the weight, improving their health even before the often challenging process of weight loss begins.

“Then, if you can disrupt this harmful signaling in combination with weight-loss strategies,” Dr. Freishtat says, “you’re really getting the best of both worlds.”

Eventually, he adds, tests might be available so that doctors can warn patients that their fat cells are sending out harmful messages before disease symptoms start. By giving patients an early heads up, Dr. Freishtat says, patients might be more likely to heed advice from physicians and make changes before it’s too late.

“If doctors could warn patients that their fat is telling their blood vessels to fill up with plaque and trigger a heart attack in 10 to 20 years,” he says, “patients might be more compliant with treatment regimens.”