U.S. Department of Health and Human Services

Workshop on Developing Precision Medicine Approaches to the Treatment of Severe Obesity in Adolescents: Research Gaps and Opportunities

9/18/2017 12:00 AM
9/19/2017 12:00 AM
Yes
No

Program Contact

Voula Osganian, MD, ScD, MPH
Division of Digestive Diseases and Nutrition, NIDDK
T: 301-827-6939
E: voula.osganian@nih.gov

Meeting Registration

Email Lauren Meskill to register
E: MeskillL@extra.niddk.nih.gov

Rockville
 
Fishers Lane Conference Center

Event Details

Workshop Booklet (PDF, 795 KB)

Background

Severe obesity in adolescents is a growing and serious concern and is associated with significant physical and psychological co-morbidities. Response to behavioral and lifestyle interventions generally show relatively small improvements in BMI that are not sustained, and the limited pharmacotherapy options available also show modest efficacy. Bariatric surgery leads to the greatest and most sustained weight loss; however, it can be associated with considerable short and long term health risks, and despite surgical intervention, many adolescents continue to have severe obesity. Little is known regarding which treatment approaches will promote meaningful and sustained weight loss in adolescents with severe obesity or how to target such treatments to maximize efficacy.

Meeting Objectives

This workshop will bring together scientists with expertise in genetics, pediatric obesity, endocrinology, epidemiology, psychology, behavioral medicine, adolescent medicine, bariatric surgery, and other disciplines to discuss and identify 1) what is known regarding the epidemiology and biopsychosocial determinants of severe obesity in adolescents, 2) what is known regarding effectiveness of treatments for severe obesity in adolescents and predictors of response, and 3) gaps and opportunities for future research to develop more effective and targeted treatments for adolescents with severe obesity. The goal of this trans-NIH workshop is to accelerate research that will identify which treatment approaches will be most beneficial for specific patients based on a better understanding of individual differences in genetic endowment, clinical, metabolic, psychological, and behavioral phenotypes, and response to environmental exposures.

Organizing Committee

Chairs

Aaron S. Kelly, Ph.D.
Associate Professor of Pediatrics and Medicine
University of Minnesota Medical School
University of Minnesota Masonic Children's Hospital

Marsha D. Marcus, Ph.D.
Professor of Psychiatry and Psychology
University of Pittsburgh School of Medicine
Western Psychiatric Institute and Clinic

Jack A. Yanovski, M.D. Ph.D.
Chief of the Section on Growth and Obesity
Program on Developmental Endocrinology and Genetics
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institutes of Health

NIH Members

NIDDK

Voula Osganian, M.D., Sc.D., M.P.H.
Andrew Bremer, M.D.
Mary Evans, Ph.D.
Christine Hunter, Ph.D., ABPP
Robert Kuczmarski, Dr.P.H.
Barbara Linder, M.D., Ph.D.
Pamela Thornton, Ph.D.
Susan Yanovski, M.D.

NICHD

Layla Esposito, Ph.D., M.A.

NHLBI

Charlotte Pratt, Ph.D., R.D.

OBSSR

Deborah Young-Hyman, Ph.D.

ODP

Rachel Ballad, M.D., M.P.H.

Registration Deadline

September 1, 2017 or until full.

To register, RSVP to Lauren Meskill via email with your name, affiliation and phone number.​​​​

Agenda

Monday, September 18, 2017

   
7:30 a.m. – 8:15 a.m. Registration
   
8:15 a.m. – 8:20 a.m. Welcoming Remarks
Griffin P. Rodgers, MD, MACP, National Institute of Diabetes and Digestive and Kidney Diseases
   
8:20 a.m. – 8:30 a.m. Introduction and Workshop Goals
Voula Osganian, MD, ScD, National Institute of Diabetes and Digestive and Kidney Diseases

Session I

Scope of the Problem: Severe Obesity and the Adolescent

Moderator: Robert Kuczmarski, PhD, National Institute of Diabetes and Digestive and Kidney Diseases
   
8:30 a.m. – 8:50 a.m. Epidemiology of Severe Obesity in Adolescents
Cynthia Ogden, PhD, Centers for Disease Control and Prevention
   
8:50 a.m. – 9:10 a.m. Adolescent Development
Margaret Zeller, PhD, Cincinnati Children's Hospital Medical Center
   
9:10 a.m. – 9:40 a.m. Question and Answer Panel
   
9:40 a.m. – 10:10 a.m. Break

Session II

Biopsychosocial and Behavioral Factors that are Associated with the Development of Severe Obesity in Adolescents

Moderator: Deborah Hyman-Young, PhD, Office of Behavioral and Social Sciences Research Office of the Director
   
10:10 a.m. – 10:35 a.m. Psychosocial, Behavioral and Environmental Risk Factors
Elissa Jelalian, PhD, Alpert Medical School of Brown University
   
10:35 a.m. – 11:00 a.m. Genetics and Epigenetics
Sadaf Farooqi, MBChB, PhD, University of Cambridge
   
11:00 a.m. – 11:25 a.m. Hedonic Eating, Food Reward and Appetite
Ania Jastreboff, MD, PhD, Yale University School of Medicine
   
11:25 a.m. – 11:55 a.m. Question and Answer Panel
   
11:55 a.m. – 12:45 p.m. Lunch

Session III

Treatment Approaches for Severe Obesity in Adolescents

Moderator: Charlotte Pratt, PhD, National Heart, Lung, and Blood Institute
   
12:45 p.m. – 1:05 p.m. Lifestyle and Behavioral Interventions
Marsha Marcus, PhD, University of Pittsburgh School of Medicine
   
1:05 p.m. – 1:25 p.m. POWER Clinical Registry- Clinical Experience and Health Outcomes
Shelley Kirk, PhD, RD, LD, Cincinnati Children's Hospital Medical Center
   
1:25 p.m. – 1:45 p.m. Pharmacologic Interventions
Aaron Kelly, PhD, University of Minnesota Medical School
   
1:45 p.m. – 2:05 p.m. Surgical Interventions
Thomas Inge, MD, PhD, Children's Hospital Colorado
   
2:05 p.m. – 2:25 p.m. Emerging Therapies
Lee Kaplan, MD, PhD, Harvard Medical School
   
2:25 p.m. – 2:45 p.m. Developing and testing a Chronic Care Model for the adolescent with severe obesity
Stephen Cook, MD, MPH, University of Rochester Medical Center
   
2:45 p.m. – 3:15 p.m. Question and Answer Panel
   
3:15 p.m. – 3:45 p.m. Break

Session IV

Biomarkers and Phenotypes that Predict Response to Treatment in Adolescents with Severe Obesity

Moderator: Barbara Linder, MD, Ph.D., National Institute of Diabetes and Digestive and Kidney Diseases
   
3:45 p.m. – 4:05 p.m. Eating Behaviors and Psychological Phenotypes/Factors
Kerri Boutelle, PhD, University of California, San Diego School of Medicine
   
4:05 p.m. – 4:25 p.m. Physical Activity Phenotypes/Factors
Molly Bray, PhD, RD, LD, The University of Texas at Austin
   
4:25 p.m. – 4:45 p.m. Biomarkers
Charles Burant, MD, PhD, University of Michigan
   
4:45 p.m. – 5:15 p.m. Question and Answer Panel
   
5:15 p.m. Closing Remarks Day 1 from Co-Chairs
   

Tuesday, September 19, 2017

   
8:00 a.m. – 8:15 a.m. Opening Remarks and Goals for Day 2
Voula Osganian, MD, ScD, National Institute of Diabetes and Digestive and Kidney Diseases
   
8:15 a.m. – 9:30 a.m. Breakout Sessions
  1. Epidemiology and Subgroups at Risk including Disparities and Special Populations

    Leader:  Cynthia Ogden, PhD, Centers for Disease Control and Prevention
    Facilitator:  Pamela Thornton, PhD, National Institute of Diabetes and Digestive and Kidney Diseases

  2. Biopsychosocial and Behavioral Factors Associated with the Development of Severe Obesity

    Leader:  Elissa Jelalian, PhD, Alpert Medical School of Brown University
    Facilitator:  Mary Evans, PhD, National Institute of Diabetes and Digestive and Kidney Diseases

  3. Treatment Approaches for Severe Obesity in Adolescents

    Leader:  Stephen Cook, MD, MPH, University of Rochester Medical Center
    Facilitator:  Barbara Linder, MD, PhD, National Institute of Diabetes and Digestive and Kidney Diseases

  4. Biomarkers and Phenotypes that Predict Response to Treatment

    Leader:  Charles Burant, MD, PhD, University of Michigan
    Facilitator:  Sue Yanovski, MD, National Institute of Diabetes and Digestive and Kidney Diseases
   
9:30 a.m. – 9:45 a.m. Break
   
9:45 a.m. – 10:45 a.m. Breakout Session Subgroup Presentations by Leaders (15 min each)
   
10:45 a.m. – 11:45 a.m. Full Group Panel Discussion led by Co-Chairs
   
11:45 a.m. – 12:15 p.m. Workshop Summary and Recommendations with Concluding Remarks from Co-Chairs
   
12:15 p.m. Wrap up and Adjournment
Voula Osganian, MD, ScD, National Institute of Diabetes and Digestive and Kidney Diseases
   

Directions/Travel

Hotel Accommodations

Hilton Washington DC/Rockville Hotel & Executive Meeting Center
1750 Rockville Pike
Rockville, MD  20852

Website:  http://www3.hilton.com/en/hotels/maryland/hilton-washington-dc-rockville-hotel-and-executive-meeting-ctr-IADMRHF/index.html
(More hotel information can be obtained from the website above. To make a hotel reservation, use the link under 'Government Room Rate' below.)

Government Room Rate

A limited block of sleeping rooms for meeting participants has been reserved at the Hilton Washington DC/Rockville Hotel & Executive Meeting Center. The rate is the prevailing government rate of $231 per night for single occupancy, plus tax (13%). To reserve a hotel room at the group rate, click on the link to book your group rate for the Workshop on Developing Precision Medicine Approaches to the Treatment of Severe Obesity in Adolescents: Research Gaps and Opportunities Meeting. The room block will be in effect at the Government rate only until Sunday, August 27, 2017, or until full, whichever comes first. Any room reservations received after this date will be accepted on a space and rate-availability basis.

Reservation Dates

Book arrival on Sunday, September 17, 2017, and departure on Tuesday, September 19, 2017. If you require alternate dates, please send an email to Lauren Meskill at MeskillL@extra.niddk.nih.gov. Any alternate date requests will need to be approved through the NIDDK.

Check-in

Please be certain that the hotel provides you with a confirmation number for your reservation. After August 27, 2017, the official room block will be released, and the hotel may charge significantly higher rates and may be sold out. When making a reservation, please provide your room and bedding preferences. The hotel will assign specific room types at check-in, based on availability. Please be advised that requests are not guaranteed. Check-in time is 4:00 p.m., and checkout time is 12:00 p.m.

Cancellations

If you need to cancel your reservation, please do so by 4:00 p.m. on the day prior to arrival, or you will be charged a no-show fee for 1 night on your credit card.

NIH Visitor Information 

Information on visiting the NIH, campus maps, shuttle schedules, driving directions, security, and more can be found on the NIH Visitor Information page.​​​

Minutes

Minutes are currently unavailable.

Attendees

Attendees are currently unavailable.

Abstracts

SESSION 1: Scope of the Problem: Severe Obesity and the Adolescent

Epidemiology of severe obesity in US adolescents
Cynthia L Ogden, PhD

In the United States, severe obesity among youth aged 2-19 years is often defined as 120% of the 95th percentile on the sex-specific 2000 CDC BMI-for-age growth charts. Some researchers had used the 99th percentile to define severe obesity but the CDC growth charts do not extend beyond the 97th percentile. Consequently, a percentage of the 95th percentile (the definition of obesity) was recommended for monitoring growth in youth with very high BMIs. Recently, cut points reflective of 120%, 130%, 140% and 150% of the 95th percentile of BMI-for-age have been proposed to be added to clinical growth charts. These charts will be announced in the Federal Register in the Fall of 2017. Following the Federal Register Notice, the charts, along with a detailed report, will be posted on the CDC growth charts website. There are differences in body fat by race/Hispanic origin within BMI categories. Non-Hispanic black youth have less body fat than non-Hispanic white and Hispanic youth. Research indicates that health risk for Asian adults begins at lower BMI values than the traditional adult cut points of 25 and 30. In fact, in Taiwan, obesity for adults is defined at 27 instead of 30. Additional research may be needed on defining severe obesity in Asian American youth

Estimates of severe obesity from the National Health and Nutrition Examination Survey (NHANES) indicate that in 2013-2014, 9.1% of US adolescents aged 12-19 years had severe obesity, triple the prevalence in 1988-1994. Obesity prevalence doubled among adolescents over the same time period from about 10 to 20%. Disparities in prevalence of severe obesity exist. Based on data from 2011-2014, the prevalence of severe obesity was 11.6% among non-Hispanic black, 8.8% among Hispanic, 6.7% among non-Hispanic white and 2% among non-Hispanic Asian adolescents 12-19 years of age. Unlike in adults the prevalence of severe obesity was higher for non-Hispanic black compared to non-Hispanic white adolescents for both males and females.

Adolescent Development
Meg Zeller, PhD

Developmental science provides a framework where adolescence is uniquely characterized as a period of rapid change in physical, emotional, interpersonal, social, and cognitive domains. Adolescence is also a period distinguished by an increase in behaviors considered to be risky and/or harmful and of high public health concern. Some teens navigate this period relatively unscathed, while others are launched on a trajectory of increasing burden and risk in young adulthood. Within this context, the provision of health care and the management of chronic health conditions, specifically, can be uniquely challenged. Adolescence is a known period of higher non-adherence to self-management regimens and treatment session non-attendance, with known contributors ranging from aspects of the developing brain (i.e., executive functioning, reward-seeking, impulse control), their navigating increased independence from caregivers, or alternately, aspects of emotional well-being or social support. Our empirical understanding of the adolescent with severe obesity and effective treatments have not grown at the pace of the epidemic. Nonetheless, there are important extant data from the broader literature as well as emerging data which highlight areas of vulnerability (versus normative adolescent risk) for this obesity sub-population that can inform the design and execution of effective treatments to improve weight, health, and psychosocial outcomes

SESSION 2: Biopsychosocial and Behavioral Factors that are Associated with the Development of Severe Obesity in Adolescents

Psychosocial, Behavioral, and Environmental Risk Factors
Elissa Jelalian, PhD

Retrospective and longitudinal studies provide evidence that growth trajectories of adolescents with severe obesity may be identified with some degree of accuracy from a fairly young age. For example, there is work to suggest that children with severe obesity at 6 years of age may be distinguished from those who are healthy weight by as early as 4 months, and that severe obesity during school age has a high probability of persisting into adolescence. While these trajectories have been identified, relatively little work has been conducted to determine the environmental, behavioral, and psychosocial factors that serve to promote or mitigate the risk of remaining on such a pathway. Research supports the importance of lifestyle behaviors such as dining out, consumption of sugar sweetened beverages, reduced sleep, and sedentary behavior, as well as socioedemographic and psychological factors, in the development of obesity in children and adolescents; however, virtually none of this work focuses on risk for severe obesity and few studies even identify severe obesity as a distinct outcome. Research is needed to understand whether severe obesity during adolescence results from incremental cumulative risk among these better examined factors or constitutes a qualitatively different trajectory with a unique set of risk factors.

There is an emerging body of evidence examining behavioral and psychosocial correlates of severe adolescent obesity, focused primarily on teens seeking weight loss surgery. While this work provides important information regarding potential risk factors for the development and maintenance of severe obesity, the cross-sectional nature of the research limits its predictive value. There is a clear need for longitudinal studies to identify sociodemographic, behavioral, and psychosocial influences that place children at risk for severe obesity from an early age, with specific attention to the interaction between these characteristics and genetic and epigenetic factors. Further, conceptual models derived from this work should be developmental, such that risks and opportunities may be identified at multiple points in development.

Hedonic Eating/Food Reward and Appetite Regulation and the Development of Severe Obesity in Adolescents
Ania Jastreboff, MD, PhD

The role of the brain is critical in controlling eating and a complex interplay exists within neural networks implicated in reward-motivation (striatum), hunger-satiety (hypothalamus), and decision-making (prefrontal cortex) to control food consumption. Notably, the prefrontal cortex is not fully developed in adolescents, continuing to develop through adolescence into early adulthood. Brain maturation and strengthening of connectivity between the prefrontal cortex and hedonic and homeostatic brain regions and networks occurs through changes in neural branches and synapses so as to achieve higher order executive regulatory capacity over impulse control, choices, and decision-making. An important aspect of the prefrontal cortical brain maturation process is that it strengthens regulation of and connectivity with hypothalamic and striatal (reward-motivation) regions of the brain, including the nucleus accumbens part of the striatum which has been implicated in processes that lead to addiction. Indeed, adolescence is a time of increased risk-taking behavior and as is evident in addiction literature, adolescents may be particularly vulnerable to the effects of rewarding substances and potentially rewarding highly palatable foods, such as those containing sugar. This appears to be related to immature functional development of the prefrontal cortex in the setting of relatively more mature striatal-limbic regions. Thus, adolescents are potentially more vulnerable to excessive intake of highly palatable rewarding foods (e.g. high in sugar) which promote weight gain and obesity. Additionally, pubertal changes, which occur during adolescence, involving metabolic changes (e.g. insulin, leptin, etc.), may also impact neural responses and affect eating behavior and food consumption. There is evidence that these developing brain networks in adolescents are altered in the setting of obesity, particularly in response to rewarding food cues and consumption of sugar (glucose). It is not known whether metabolic changes due to weight gain and severe obesity alter the normal developmental process of these neural networks and the neuro-metabolic processes that support healthy food intake throughout childhood and adolescence. There is clearly a need for better understanding of the impact of pubertal (physiologic) and adolescent (bio-psycho-social) development on weight-related metabolic changes and obesity and its impact on brain development and resulting behavioral implications. Additionally, there is a need for mechanistic (translational) and longitudinal cohort studies of children and adolescents with and without obesity to assess the effects of weight gain and obesity on metabolism, cognition, and obesity-related diseases throughout the lifespan.

SESSION 3: Treatment Approaches for the Adolescent with Severe Obesity

Lifestyle and Behavioral Interventions
Marsha D. Marcus, PhD

Intensive lifestyle interventions for school-aged children with moderate obesity are efficacious and associated with improvements in health-related parameters, which has led to recommendations that children and adolescents with obesity be offered or referred for intensive behavioral weight loss interventions (US Preventive Services Task Force, 2017). Nevertheless, accumulating evidence has documented that lifestyle interventions are less effective for adolescents and those with severe obesity. Few randomized trials have focused on lifestyle interventions for youth with severe obesity, but available data have shown that weight losses are modest, at best, and are not sustained over time. Despite these findings, future research to enhance the impact of lifestyle interventions is crucial. Adolescents with severe obesity are likely to remain so and suffer an increasing health risk burden over time. Importantly, even very modest weight losses have been shown to be associated with positive effects on cardiometabolic risk factors over a two-year period, and thus successful intervention may serve to mitigate health risk over time. In an age of precision medicine, it is important to consider whether any sub-group of adolescents with severe obesity respond differentially to lifestyle intervention. The search for robust socio-demographic predictors of positive response has been disappointing, but there is consistent evidence that session attendance defined as > 75% of planned sessions, which has served as a proxy for intervention adherence, is positively associated with weight loss outcomes. Available data also show that adherence to self-monitoring, a key component of behavioral interventions, is unsatisfactory. Thus, future research to identify strategies to improve adherence to lifestyle interventions is indicated. Additional work to identify individuals (e.g., those with psychiatric comorbidity) who may benefit from alternative or additional intervention components is warranted. Finally, it is imperative to examine how to combine and sequence lifestyle interventions with other treatment modalities in the service of developing chronic-care interventions for these high-risk adolescents.

POWER Clinical Registry- Clinical Experience and Health Outcomes
Shelley Kirk, PhD, RD, LD

The Pediatric Obesity Weight Evaluation Registry (POWER) was established in 2013 and is comprised of 31 multi-component pediatric weight management programs, serving youth with obesity ages 18 and younger. The goal of POWER is to identify and promote effective intervention strategies for pediatric obesity. Data from the registry were used to investigate improvement in weight status and its association with patient characteristics and program exposure features. We will present results from our analyses of treatment-seeking adolescents with obesity (ages 12-18; N=2,999) and discuss important research needs going forward.

Pharmacologic Interventions
Aaron S. Kelly, PhD

Numerous medications have been evaluated for the treatment of adolescent obesity. Unfortunately, the benefit/risk profile of pharmacotherapy is questionable owing to the relatively modest efficacy of the individual medications investigated to date. The burgeoning pipeline of obesity medications currently in development for adults offers hope that safe and effective agents will be available for pediatric use within the next 5-10 years. As the field of pediatric obesity medicine continues to mature, identifying predictors of response and implementing adaptive clinical protocols will maximize benefit while minimizing risks of pharmacotherapy.

Surgical Interventions
Thomas Inge, MD, PhD

This presentation will discuss how precision medicine relates to precision surgery, and emphasize that as currently practiced, weight loss surgery is not a “precision” intervention. Meaning, there is little information available to aid surgeons in use of the “right operation for the right patient.” We will review what is known regarding the effectiveness of surgical treatment for severe obesity in adolescents based on two sizable cohort studies from Sweden and the USA. In addition, the “hidden” heterogeneity in the weight/BMI change response will be highlighted and discussed. This heterogeneity in BMI response of adolescents to surgical treatment will be compared to that of adults to note similarities and differences. The possible existence of individual subpopulations with differential BMI response to surgery will also be noted, as defined statistically using latent class growth modeling of Teen-LABS data for those adolescents treated by roux en Y gastric bypass and vertical sleeve gastrectomy. With these findings, the presentation will hopefully drive a robust discussion of the potential factors predictive of membership in the latent classes of response in an effort to accelerate future research that will consider 1) how more detailed preoperative phenotyping (eg., genetic background, clinical, metabolic, psychological, and behavioral phenotypes) may be used to improve patient selection criteria, and 2) how to better understand latent factors that portend poorer surgical response might lead to early and successful use of adjunctive behavioral, pharmacologic, or other therapies to maximize treatment responses.

Emerging Therapies
Lee Kaplan, MD, PhD

Regardless of the proximal contributors – environmental, behavioral, developmental and/or genetic – disrupted regulation of energy balance and defended energy stores (fat mass) is the final common pathway in the pathophysiology of obesity. Because maintenance of an appropriate and stable fat mass in the face of widely varying nutrient sources and energy demands is critical to normal human biology, numerous genes, signaling pathways and biochemical mechanisms contribute to metabolic homeostasis. Disruption in any one or more of these mechanisms has the potential to cause or exacerbate obesity, generating a panoply of different clinically relevant subtypes of obesity, each with its own phenotypic characteristics. The heterogeneity of these multiple obesity subtypes underlies the profound patient-to-patient variation observed in response to all anti-obesity therapies, whether based in lifestyle change, pharmacology or bariatric surgery. The wide variability in obesity subtype and individual patient response limits the effectiveness and applicability of any single anti-obesity therapy, necessitating development and use of multiple treatments with distinct, and complementary, mechanisms of action. With our growing understanding of the biological underpinnings of obesity, multiple new therapies are currently being developed. They include (1) novel lifestyle-based treatments targeting environmental contributors other than diet and physical activity, (2) novel pharmacological therapies that influence relevant, newly-discovered biochemical and signaling pathways, and (3) novel endoscopic, vascular and neurostimulatory therapies aiming to exploit our growing understanding of the physiological mechanisms underlying the effectiveness of bariatric and metabolic surgery. Because these therapies target distinct and complementary mechanisms, their concurrent use in different combinations hold the promise of additive or synergistic benefits. Growing clinical experience with such combination therapy has provided important support for this approach, but controlled studies in different populations are required to determine the most effective of the many combinatorial possibilities. Ultimately, as with other complex, chronic and heterogeneous diseases, optimal treatment will likely result from matching each patient with the treatment or treatments most effective for him or her. Achieving this goal will benefit from more accurate predictors of therapeutic and potential adverse outcomes of each treatment modality. Many current studies are aimed at identifying demographic, clinical, biomarker and genetic predictors of response to each anti-obesity therapy that are powerful enough to guide clinical decision-making. Looking to the future, it is likely that our effectiveness in treating obesity will be most strongly enhanced by (1) our growing recognition and appreciation of the heterogeneity of obesity, (2) greater understanding of the biological basis of effective treatment, (3) the accelerating emergence of new therapies, (4) the increasing embrace of combination therapy, and (5) a greater focus on identifying and applying predictors of clinically relevant therapeutic response.

Developing and testing a Chronic Care Model for the adolescent with severe obesity
Stephen Cook, MD, MPH

The Chronic Care Model focuses on improving patient self-management, but it has been tested and applied from the Quality Improvement science/methodology side or as part of a clinical focused strategy. The CCM incorporates health system level changes within the context of community policies to support practices/providers as well as patients toward change. The CCM focuses on 3 main goals 1) creating informed/activated patients; 2) created informed/activated providers; and 3) improve patient self-management for improved health outcomes. Improving a patient’s ability to self-manage a disease has used Behavior Economic approaches or external rewards or punishments with minimal effect on long term change. Strategies aimed at improving patient and provider autonomy are lacking and Self-Determination Theory represents a behavioral approach that is uniquely for application within precision medicine research. Lastly, obesity is the most stigmatized and biased condition in America and this must be examined both from the provider standpoint and the patient (teen) and parent standpoint. There are a number of child focused research networks that could serve as real-world laboratories to test treatment interventions for teens with severe obesity.

SESSION 4: Biomarkers and Phenotypes that Predict Response to Treatment in Adolescents with Severe Obesity

Eating Behaviors and Psychological Phenotypes/Factors
Kerri Boutelle, PhD

The prevalence of severe obesity in youth is increasing and affects between 4% and 6% of the population. Despite the serious immediate and long-term comorbidities, current treatments are limited in effectiveness. Data with children, adolescents and adults shows that not all individuals who participate in weight loss programs lose a clinically significant amount of weight, and of those who lose weight, many do not retain the weight loss. Recently, the field is beginning to understand that individuals with overweight and obesity are a heterogeneous group and that individual differences may contribute to both overeating and weight gain, and responsiveness to weight loss programs. Although many research studies evaluate and control for individual factors, these strategies cannot address multiple factors acting in concert. This presentation will review the psychological and eating behaviors that contribute to eating beyond nutritional needs and weight gain. The literature regarding the psychological and eating phenotypes in children, adolescent and adults will be reviewed, as well as some of our own emerging data on food and satiety responsiveness. Finally, I will review the strengths and weaknesses of analyses used to evaluate phenotypes, and next steps for the field. It is important that this knowledge is used to determine specific psychological and eating phenotypes among adolescents with severe obesity, to ultimately develop targeted and effective treatment programs.

Physical Activity Phenotypes/Factors in Adolescent Obesity
Molly S. Bray, PhD

An imbalance between energy intake and energy expenditure is at the heart of the development of obesity – a person cannot become obese without consuming more energy than he/she is expending. Nevertheless, the processes that control the physiological partitioning of both energy intake and expenditure are more complex than merely those related to eating and exercise. It is often assumed that adolescents with severe obesity are not capable of being physically active; however, many studies have reported successfully engaging severely obese children and teens in physical activity. In fact, adolescents with severe obesity are often very strong, as the act of simply moving a large body through space can strengthen skeletal muscle. Unfortunately, muscular strength is often accompanied by low fitness and musculoskeletal joint pain in adolescents with severe obesity, due in part, to excessive stress on potentially still-developing bones. Thus, exercise programs designed for adolescents with severe obesity should include activities that take advantage of the child’s strength, while considering potential joint or fitness limitations (e.g., rope swing, tire pull, swimming). While the “output” or physical activity side of the energy balance equation generally has less impact on weight gain and loss than dietary intake, it may play a critical role in the prevention of obesity-related co-morbidities; thus, encouraging physical activity and exercise in adolescents with severe obesity is important. Regrettably, behavioral/lifestyle interventions that include physical activity and/or dietary modification are associated with limited long-term success, particularly in children with severe obesity. Poor adherence is often a key factor in the lack of response to behavioral interventions, and understanding how to prevent program dropout is a critical component of improving intervention efficacy. For adolescents who voluntarily enrolled in a 15-week aerobic exercise regimen, physiological factors that predicted exercise dropout included obesity severity, low fitness, depression, age, anxiety, waist circumference, and percent body fat. In addition, exercise adherence and exercise tolerance had a substantial genetic component. SNPs in 10 genes exceeded a genome-wide significance of p<10-4.5 for exercise dose, including FN3KRP, FAM148A, CUX2, RIPK2, ABCB11, B3GNTL1, BRE, BDNF, ZHX3, IDE, and TBCD. Pathways contributing to lipid metabolism, neural signaling, muscle contraction, and adiposity were significantly represented by SNPs with a nominal p<0.0001. The brain-derived neurotropic factor (BDNF) signaling pathway emerged as a central factor linking multiple other pathways, highlighting neural signaling as a target for exercise tolerance. As with other phenotypes associated with severe obesity, the complex interaction of both genetic and non-genetic factors combine to influence both physical activity behavior and response to exercise interventions in adolescents. More research is needed to examine how exercise can promote weight loss, and in turn, how physical activity patterns change as adolescents with severe obesity begin to lose weight.

Biomarkers
Genetic and epigenetic programming of altered metabolism and its association with oxidative capacity and the development and maintenance of obesity
Charles Burant, MD, PhD

The incidence of obesity has risen markedly and studies have provided a genetic framework for understanding obesity. More recently, the contribution of epigenetic programming and its potential role in the regulation of gene expression. Observational studies in humans and experimental animal studies have shown that altered nutrient exposures in utero can result in transgenerational alterations in weight trajectories and affect the risk of metabolic diseases, including type 2 diabetes and cardiovascular disease. High intrinsic oxidative capacity (VO2max) is positively related to human lifespan and negatively related risks of obesity, diabetes and cardiovascular disease regardless of age, sex, race, and other risk factors. Multiple studies have shown that intrinsic (genetically driven) oxidative capacity, rather than exercise-associated increases in VO2max is the primary determinant of an individual’s cardiometabolic health. I will show that genetic selection for oxidative capacity in an animal model affects mitochondrial fatty acid and amino acid fuel utilization and provide evidence that in humans, similar alterations in metabolism related to oxidative capacity can be identified. I will also provide data that signals of altered nutrient utilization can be found in adolescents by plasma metabolomics profiling. Finally, I will present preliminary evidence that intrauterine nutrient exposures can affect fetal growth and generate a reflection of altered fuel metabolism in fetal cord blood. I will present a model that will suggest that genetic and epigenetic mechanisms work in concert to affect metabolism that may predispose to life-long obesity risks.​

Location

Line
  • 5635 Fishers Lane
  • Rooms 508/509
  • MD 20852
Webinar

Contacts

Line

Program Contact

Voula Osganian, MD, ScD, MPH
Division of Digestive Diseases and Nutrition, NIDDK
T: 301-827-6939
E: voula.osganian@nih.gov

Meeting Registration

Email Lauren Meskill to register
E: MeskillL@extra.niddk.nih.gov