Ania M. Jastreboff, Ph.D. - US grants

DESCRIPTION (provided by applicant): The purpose of the K23 research study is to define the mechanisms by which increased levels of insulin affect brain regions involved in food reward-motivation and influence eating behavior. This study will provide critical data necessary for the investigation of novel treatments that target attenuating the effects of hyperinsulinemia on the brain, in order to curb food cravings and excess energy intake, thereby diminishing weight gain. The specific aims of this research project are to investigate the effect of insulin on neural responses to food cues and eating-behaviors in overweight/obese and lean individuals and to assess the influence insulin resistance has on these neural mechanisms and food intake. The study is a cross-sectional, experimental study assessing neural responses in reward-motivation, decision-making, and homeostatic brain regions in response to acute, peripheral administration of insulin. While undergoing hyperinsulinemic-euglycemic clamp vs. saline-euglycemic control, functional magnetic resonance imaging (fMRI) scans will be conducted to assess neural responses in 30 overweight/obese and 20 lean individuals during viewing of high-calorie food pictures. Each of the 50 subjects will undergo hyperinsulinemic-euglycemic- and saline-euglycemic- fMRI procedures in randomized fashion on two separate days. Food craving and hunger will be assessed throughout the experiment and food intake will be measured following both the hyperinsulinemic-euglycemic- and saline- euglycemic- fMRI procedures. The role of insulin resistance on the observed neural responses and on eating behavior will also be investigated. Results obtained from this study will provide insight into how insulin affects neural mechanisms and eating behaviors in obese and lean individuals and help determine the role insulin resistance may play in these mechanisms. This study will contribute to the understanding of pathophysiologic mechanisms involved in obesity and has the potential to impact interventions for obesity and type 2 diabetes by elucidating therapeutic targets to attenuate food craving and intake of high-calorie foods. Additionally, the proposed project and vital behavioral-neuroscience training will provide the candidate with the data and knowledge required for a successful R01 application. The goals of this proposal are consistent with the Strategic Plan for NIH Obesity Research to discover fundamental biological processes that regulate body weight and influence behavior and to understand the factors that contribute to obesity and its consequences. Elucidating how insulin affects neural mechanisms and eating behaviors in obese individuals and determining the role insulin resistance and hyperinsulinemia may play in these mechanisms will significantly contribute to understanding pathophysiologic mechanisms involved in obesity and high-calorie food consumption, as well as potentially impact therapeutic interventions for obesity and type 2 diabetes.

ABSTRACT The United States is at the forefront of the global obesity epidemic. To understand the mechanisms driving increases in obesity, this first cycle of the R01-DK099039 project developed and validated a novel laboratory model for overeating highly palatable (HP) foods in the context of HP food cue and stressful environments, both of which are associated with weight gain and obesity risk. Findings supported that BMI-related adaptations in cortisol, ghrelin, insulin sensitivity, HP food craving and hunger each predicted HP overeating in a Food Snack Test (FST) in a laboratory experiment, and remarkably, these measures also prospectively predicted weight gain over a longitudinal 2-year outcome period. Recent data suggests glucagon-like peptide-1 (GLP-1) modulates stress biology along with its effects on metabolism. Preliminary work by led by Dr. Jastreboff indicate GLP-1 analogue (GLP-1a) treatment decreases craving, hunger and food intake in both the laboratory and real-world setting. Thus, in this competitive renewal, we propose a multi-PI experimental therapeutics approach with the GLP-1a, semaglutide, in the unique and predictive laboratory model developed in the current project to test the hypothesis that GLP-1a treatment will attenuate HP food cue- and stress-induced food motivation and intake in obesity and also improve metabolic and stress responses and such changes will predict weight outcomes. A randomized, double-blind, placebo-controlled 12-week study with GLP-1a in men and women (N=96) with obesity (BMI 30-39.9 kg/m2) is proposed to test the above overall hypothesis both in a laboratory experiment and over a 12 -week treatment period to assess real-world outcomes. Specific aims are: 1) to examine the effects of GLP-1a vs. PBO treatment on food craving, hunger, food-cue- and stress- induced FST intake and eating topography in the FST; 2) to assess the effects of GLP-1a vs. PBO treatment on weekly food craving and food calorie intake in the real-world setting during the 12-week treatment period; and 3) to examine the effects of GLP-1a treatment on metabolic and stress responses (ghrelin, cortisol, and insulin resistance) on HP food craving and intake in the experimental lab model of food craving and FST intake. Exploratory aims will GLP-1a changes in laboratory outcomes predict weight outcomes and whether specific factors such as gender, chronic stress, disordered eating, diet and physical activity affect outcomes. Utilizing a novel experimental therapeutics approach, the next phase of this project will apply the current cycle?s validated laboratory model of identifying processes underlying greater HP food craving, intake and weight gain to test mechanisms by which a GLP-1a analogue exerts significant weight effects in obesity. Positive findings will not only inform how GLP-1a exerts effects on weight, but also provide a unique, stress and food cue sensitive, innovative and cost-effective human laboratory approach for testing novel therapeutics to decrease HP food craving, overeating and weight gain.

ABSTRACT Childhood obesity is a significant public health problem that predisposes to adult obesity and serious obesity-related diseases. Obesity is particularly common in low-income families and children of obese parents, who also report higher levels of stress. High stress in parents is associated with decreased physical activity, overeating, and increased weight in parents and their children. While nutrition and behavioral preventions have been tested for low-income families, parent stress has not been targeted in highly stressed, low-income obese parents of at-risk preschoolers. In a previous pilot R21 project, we developed a novel program, Parenting Mindfully for Health, that targets parent stress and includes Nutrition and physical activity counseling (PMH+N), to reduce stress, improve parenting and healthy family choices to prevent childhood obesity in 2-5-year-old children. Findings indicated that PMH+N is feasible, acceptable, and improved parent stress and parenting to prevent increases in child body mass index (BMI) percentile relative to the contact Control with Nutrition (C+N). Building on promising preliminary findings, we now propose a 5-year R01 project to assess PMH+N vs. C+N in a large sample of parent-child dyads, and including a long-term 2-year follow-up to establish enduring effects of PMH+N on reducing parent stress, improving parenting to promote healthy eating and physical activity (PA) in parents and children, and in turn, prevent childhood obesity risk in preschoolers from highly-stressed, low- income families. Low-income, highly-stressed, obese parent-child dyads (N=240, children aged 2-5) will be randomly assigned to receive a 12-week PMH+N or C+N intervention and participation in a Toy Wait Task(TWT) challenge to assess observed parent-child interaction as a bio-behavioral measure pre/post intervention to assess parenting and stress responses. The following specific aims will be addressed: (1) test the efficacy of 12-week PMH+N vs. C+N in reducing parent stress and improving parenting and health behaviors in parent and child to decrease childhood obesity risk; (2) examine parent stress response, observed parenting, and family food intake and physical activity as mediators of PMH+N vs. C+N effects on parent and child BMI; (3) examine the enduring effects of PMH+N vs. C+N on parenting and health behaviors and child BMI percentile in reducing obesity risk over a 2-year follow-up period; and (4) examine the enduring effects of changes on parent stress, parenting and health behaviors, parent weight and metabolic functioning post intervention during 2-year follow-up. Successful completion of the proposed interdisciplinary project will provide support for an innovative approach to decrease early childhood obesity risk in low-income, stressed families while also addressing stress and obesity in high-risk adult parents. Findings will provide critical longitudinal data on parent stress and family and parenting factors in the development of obesity in at-risk children, that may inform future public health interventions to curb the growing epidemic of obesity in children and adults.