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Principal Investigator: JACK A. YANOVSKI
Organization: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
Fiscal Year: 2024
Award: $2,333,586
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Obesity and its associated comorbid conditions (1) continue to be major issues among children in the United States. We continue to examine genes involved in the leptin signaling pathway to identify gene variants impacting body composition, with the expectation that improved understanding might help the development of precision medicine approaches for obesity. We are currently intensively studying a variant MC3R that is associated with adiposity in children and which appears to have functional significance for MC3R signal transduction. Children and adults who are homozygous for two rare polymorphisms (Thr6Lys and Val81Ile) have significantly greater fat mass and leptin compared with wild type or heterozygous children. Ongoing studies attempt to understand the mechanisms by which these sequence alterations impact body weight. We have therefore created novel knock-in mice expressing the human wild type MC3R(hWT/hWT) and human double-mutant MC3R(hDM/hDM). MC3R(hDM/hDM) have greater weight and fat mass, increased energy intake and feeding efficiency, but reduced fat-free mass compared with MC3R(hWT/hWT). MC3R(hDM/hDM) bone- and adipose tissue-derived mesenchymal stem cells (MSCs) differentiated into adipocytes that accumulated more triglyceride than MC3R(hWT/hWT) MSCs. MC3R(hDM/hDM) impacted nutrient partitioning to generate increased adipose tissue that appeared metabolically healthy. These data confirmed the importance of MC3R signaling in human metabolism and suggested a previously-unrecognized role for the MC3R in adipose tissue development. Current studies are seeking to understand better the roles of MC3R in peripheral metabolism including studies of hepatic autophagy. We have been using a floxed Mc3r mouse, which has allowed us to study tissue-specific knockouts of Mc3r in hepatocytes, with studies of other cell types currently underway.
We have previously found that leptin is an important predictor of weight gain in children and identified children with hyperleptinemia and leptin receptor mutations. We have also found hyperleptinemia out of proportion with body fat mass in children with psychological loss of control (LOC) over-eating. Such data suggest the importance of leptin resistance as a factor associated with weight gain and have led to recent explorations of other syndromes accompanying obesity that may cause dysregulation of leptin signaling, including WAGR, Bardet-Biedl (2), PCSK1, Leptin Receptor deficiency, and other conditions such as Smith Magenis Syndrome (3). Current studies are directed at understanding additional genetic, physiological, and psychological factors that place children at-risk for undue weight gain (4-X), including humoral factors (4), alterations in energy balance (5-6), stool microbiome (7) socioeconomic (8-9) and environmental factors including the COVID-19 pandemic (10), familial factors (11) food reinforcement and inhibitory control (12), negative affective states (13-14), and disinhibited eating (15-18). For examples, over a mean follow-up from baseline of 8.5 years, adjusting for covariates and repeated measures of BMI or fat mass, weight-based teasing was associated with greater gain of BMI and fat mass across the follow-up period (ps .007). Adjusting for covariates, youths reporting high weight-based teasing (two standard deviations above the mean) experienced a 33% greater gain per year in BMI and a 91% greater gain in fat mass per year compared with peers who reported no weight-based teasing. In contrast, we found no association between diurnal fluctuations in serum leptin and weight or fat mass changes (7).
Investigations concentrating on binge eating behaviors in children suggest that such behaviors are also associated with adiposity in children and predict future weight gain in children at-risk for overweight. Two completed protocols examined efficacy of interpersonal therapy (IPT) as a weight gain preventive strategy among children and adolescents who report binge eating behaviors versus a control health education (HE) program (16). Among girls with high self-reported baseline social-adjustment problems or anxiety, IPT, compared to HE, was associated with the steepest declines in BMIz (p<.001) and fat mass (p<=.03). In obesity-prone adolescent girls, IPT was associated with improvements in BMIz over 3 years among youth with high social-adjustment problems or trait anxiety. Youth with remission of Loss of Control (LOC) eating at end-of-treatment had lower serum glucose, higher high-density lipoprotein cholesterol and lower triglycerides at 6-month follow-up when compared with youth with persistent LOC. Thus, reducing LOC eating in adolescent girls may have a beneficial impact on some components of the metabolic syndrome. A new study to examine if retraining attentional biases away from palatable foods can help children avoid weight gain has completed data collection and results are being prepared for publication in the next few months.
Given the rapid increase in the prevalence of obesity and its association with metabolic complications (1), the development of treatments for obesity is urgently needed (19). We have conducted translational trials related to modulation of the leptin signaling pathway using the melanocortin agonist called setmelanotide. Our data suggest that the leptin resistance of patients with the rare obesity-causing disorder Bardet Biedl syndrome is treatable with setmelanotide (2), which was recently approved for use in this condition by the Food and Drug Administration. Similar studies have not identified marked improvements in body weight in patients with Smith-Magenis Syndrome given setmelanotide (3), implicating involvement of signaling molecules that work further downstream of leptin signaling, including brain-derived neurotrophic factor, as etiologic factors for the obesity of Smith-Magenis Syndrome. We have also completed a randomized controlled study examining the use of diazoxide choline-extended-release for the obesity of people with the Prader-Willi syndrome an open-label extension, and a randomized controlled medication withdrawal phase, with the data suggestive of efficacy for those with significant hyperphagia (20-22) that have led to this medication receiving a Breakthrough Therapy designation from the FDA and a New Drug Application being submitted for consideration in 2024. Finally, we have conducted studies to examine the hypothesis that administration of colchicine can decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation (7, 23). 40 Adults with obesity were randomized to colchicine 0.6 mg or placebo capsules twice daily for 3 months. Compared with placebo, colchicine significantly reduced C-reactive protein (P <0.005), erythrocyte sedimentation rate (P <0.01), white blood cell count (P <0.005), and absolute neutrophil count (P <0.001). Changes in homeostatic model assessment of insulin resistance (P = 0.0499), fasting insulin (P = 0.07) and glucose effectiveness (P = 0.08), suggested metabolic improvements in the colchicine versus placebo group. This pilot study found colchicine significantly altered adipose tissue insulin sensitivity and changed circulating mononuclear cell subpopulations towards a less inflammatory stance (23), although there were few changes in the stool microbiome (7). These results suggest a larger, adequately powered study should be conducted to determine whether colchicine improves insulin resistance and other measures of metabolic health in at-risk individuals. A large trial for this purpose is underway. Finally, we completed a pilot study of a GLP1 receptor agonist in adolescents who have undergone sleeve gastrectomy but have insufficient weight loss (24). Other collaborative publications have taken advantage of our samples of healthy youths as controls (25-28).
Terms: <0-11 years old><17p- syndrome><21+ years old><Active Follow-up><Adipocytes><Adipose Cell><Adipose tissue><Adolescent><Adolescent Youth><Adult><Adult Human><Agonist><Anxiety><Autophagocytosis><BDNF><BMI><BMI percentile><BMI z-score><Bardet Biedel syndrome><Bardet-Biedl Syndrome><Behavior><Behavioral><Binge Eating><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Serum><Body Composition><Body Tissues><Body Weight><Body Weight decreased><Body fat><Body mass index><Bone Tissue><Brain-Derived Neurotrophic Factor><C-reactive protein><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Caloric Intake><Capsules><Causality><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Characteristics><Child><Child Youth><Childhood><Children (0-21)><Choline><Colchicine><D-Glucose><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Data Collection><Development><Dextrose><Diazoxide><Disease><Disease remission><Disinhibition><Disorder><Drugs><Eating><Eating Behavior><Effectiveness><Energy Intake><Environmental Factor><Environmental Risk Factor><Erythrocyte Sedimentation Rate><Etiology><Fasting><Fat Cells><Fats><Fatty Tissue><Fatty acid glycerol esters><Female Adolescents><Food><Food Intake><Food and Drug Administration><Future><GCG><GCG gene><GLP1><GLP2><Gastrectomy><Gene variant><Generalized Growth><Genes><Genetic><Genetic Polymorphism><Genetic mutation><Glucose><Goals><Growth><H2O syndrome><HDL Cholesterol><HDL Cholesterol Lipoproteins><Health><Health Instruction><Health Tutoring><Health education><Hepatic><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Heterozygote><High Density Lipoprotein Cholesterol><HuB219><Human><Humulin R><Hyperphagia><Impairment><Individual><Inflammation><Inflammatory><Insulin><Insulin Resistance><Intermediary Metabolism><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigation><KI mice><Knock-in Mouse><Knock-out><Knockout><LDL Cholesterol><LDL Cholesterol Lipoproteins><LEP-R><LEPR Protein><Labhart-Willi Syndrome><Labhart-Willi-Prader-Fanconi Syndrome><Leptin><Leptin receptor mutation><Leptin resistance><Leukocyte Count><Leukocyte Number><Link><Lipocytes><Liver Cells><Long-term cohort><Longitudinal cohort><Longterm cohort><Low Density Lipoprotein Cholesterol><LoxP-flanked allele><Marrow Neutrophil><Mature Lipocyte><Mature fat cell><Measures><Medication><Mesenchymal Progenitor Cell><Mesenchymal Stem Cells><Mesenchymal progenitor><Mesenchymal stromal/stem cells><Metabolic><Metabolic Processes><Metabolic syndrome><Metabolism><Mice><Mice Mammals><Modeling><Modern Man><Mononuclear><Murine><Mus><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Novolin R><Nutrient><OB Receptor><OB-R><Ob Gene Product><Ob Protein><Obese Gene Product><Obese Protein><Obesity><Over weight><Overeating><Overweight><Patient Self-Report><Patients><Peripheral><Pharmaceutical Preparations><Phase><Phenotype><Physiologic><Physiological><Physiology><Pilot Projects><Placebos><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Prader-Labhart-Willi (PLW) syndrome><Prader-Labhart-Willi syndrome><Prader-Labhart-Willi-Fanconi syndrome><Prader-Willi Syndrome><Prader-Willi syndrome (PWS)><Predictive Factor><Prevalence><Preventative strategy><Prevention strategy><Preventive strategy><Proteins, specific or class, C-reactive><Protocol><Protocols documentation><Psychological Factors><Psychological reinforcement><Psychology><Publications><Quetelet index><Randomized><Receptor Protein><Regular Insulin><Regulation><Reinforcement><Remission><Reporting><Risk><Risk Marker><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Sampling><Scientific Publication><Self-Report><Sequence Alteration><Serum><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Sham Treatment><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Smith Magenis syndrome><Social Adjustment><Syndrome><Tissue Growth><Tissues><Training><Translational Research><Translational Science><Translational trial><Triacylglycerol><Triglycerides><USFDA><United States><United States Food and Drug Administration><Variant><Variation><WAGR><WT1><WT1 Gene Product><WT1 Protein><WT1 gene><WT33><Weight><Weight Gain><Weight Increase><Weight Loss><Weight Reduction><White Blood Cell Count><White Blood Cell Count procedure><Wilms Tumor 1><Wilms tumor suppressor WT1><Withdrawal><Work><Youth><Youth 10-21><active followup><adipose><adiposity><adolescent girl><adult adiposity><adult obesity><adulthood><adults with obesity><allele variant><allelic variant><alpha-Lipoprotein Cholesterol><attentional bias><autophagy><behavior phenotype><behavioral phenotyping><beta-Lipoprotein Cholesterol><biological signal transduction><body weight gain><body weight increase><body weight loss><caloric dietary content><capsule><cardiorespiratory syndrome of obesity in child><causation><cell type><child adiposity><child obesity><childhood adiposity><childhood obesity><chromosome 17p deletion syndrome><chromosome 17p monosomy><clinical translation><clinically translatable><co-morbid><co-morbidity><comorbidity><compulsive eating><compulsive feeding><compulsive overeating><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><corpulence><del(17p) syndrome><deletion 17p syndrome><determine efficacy><develop therapy><developmental><disease causation><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><endophenotype><energy balance><environmental risk><evaluate efficacy><examine efficacy><expectation><experience><fasted><fasts><fecal microbiome><feeding><floxed><floxed allele><follow up><follow-up><followed up><followup><gene function><genetic variant><genomic alteration><genomic variant><girls><heterozygosity><hypogenital dystrophy with diabetic tendency syndrome><hypotonia-hypogonadism-obesity syndrome><hypotonia-hypopigmentia-hypogonadism-obesity (HHHO) syndrome><hypotonia-hypopigmentia-hypogonadism-obesity syndrome><hypotonia-obesity-hypogonadism-mental retardation syndrome><improved><insulin resistant><insulin sensitivity><insulin tolerance><interpersonal psychotherapy><interpersonal therapy><intervention development><interventional strategy><juvenile><juvenile human><kids><knockin mice><leptin receptor><leptin-binding protein><loss of control eating><loss of control over eating><mesenchymal stromal progenitor cells><mesenchymal-derived stem cells><metabolic phenotype><metabotype><monosomy 17p><mutant><negative affect><negative affectivity><neutrophil><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><obese children><obese individuals><obese people><obese person><obese population><obese subjects><obesity development><obesity during childhood><obesity genetics><obesity in children><obesity intervention><obesity risk><obesity therapy><obesity treatment><ontogeny><open label><open label study><pediatric><pediatric obesity><peer><pilot study><placebo group><polymorphism><polyphagia><precision medicine><precision-based medicine><prevent><preventing><progenitor cell differentiation><progenitor differentiation><programs><psychologic><psychological><randomisation><randomization><randomized control study><randomized, controlled study><randomly assigned><receptor><risk for obesity><risk of obesity><risk predictor><risk predictors><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><sham group><sham therapy><social adaptation><social role><socio-economic><socio-economically><socioeconomically><socioeconomics><stem and progenitor differentiation><stem cell differentiation><stool microbiome><stool-associated microbiome><therapy development><trait><translation research><translational investigation><treatment development><treatment strategy><weights><white adipose tissue><wt gain><wt-loss><yellow adipose tissue><youngster>