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Principal Investigator: Yingchang Lu
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $714,892
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Over 40% of adults are obese in the US. Although reducing caloric intake and/or increasing physical activity can
lead to weight loss in the short to medium term in some people, they lose efficacy in the long term. Bariatric
surgeries are currently the most durable and effective treatment for obesity but substantial complications have
been reported. Pharmaceutical options for treating obesity have been very limited and not efficacious. Anti-
obesity medications generally target either central nervous system (CNS) pathways that regulate sensations of
satiety and fullness, or peripheral modulators of digestion, metabolism and lipogenesis that result in only modest
effects. One of the major challenges in developing anti-obesity medications is that our CNS (i.e., hypothalamus,
brainstem, and limbic system), which regulates appetite and food intake, substantially overlaps with those that
modulate mood, anxiety and behavior. Several CNS-acting drugs that have been developed to suppress appetite
for weight loss have adverse behavioral effects. For example, Rimonabant (endocannabinoid receptor
antagonist) and Ecopipam (dopamine receptor antagonist) precipitate severe depression and suicide ideations;
and the recent FDA-approved MC4R agonist (Setmelanotide) for individuals carrying pathogenic mutations in
POMC, PCSK1 or LEPR genes along the leptin-melanocortin pathway also incurs similar psychiatric effects in
26% patients. All of these highlight safety issues in targeting the CNS for appetite suppression. However, the
recent success of glucagon-like peptide-1 receptor (GLP1R) agonists (Liraglutide, Semagglutide, Tirzepatide,
etc.) and amylin analogs (Cagrilintide) in treating obesity without apparent CNS-related adverse effects
demonstrates the proof of principle that targeting certain parts of our CNS for weight loss can be safe, i.e.,
targeting specific neural circuits primarily in the brainstem for GLP1R agonists and amylin analogs. It also
indicates that a subset of obesity genes can be safely targeted pharmaceutically in the CNS. There has been
tremendous progress in genetic studies of obesity and adiposity traits in the past 20 years, especially led by our
Genetic Investigation of ANThropometric traits [GIANT] consortium, which has identified >1,700 adiposity loci.
These efforts offer an unprecedented opportunity to identify novel drug targets to treat obesity, a field that
urgently needs a paradigm shift. By leveraging comprehensive GWAS resources for adiposity, psychiatric traits
and addictive risk behaviors, and rich phenome information across large-scale biobanks, we propose to integrate
multi-layers of omics to identify obesity genes using whole-exome sequencing, transcriptome-wide and
proteome-wide association analyses (Aim 1), predict pharmacological effects upon targeting obesity genes using
drug-target Mendelian randomization analyses and gene-based phenome-wide association analyses (Aim 2),
and screen neuronal effects of obesity drug target genes in iPSC-derived neurons with CRISPR-based functional
genomics (Aim 3). Our work will identify novel obesity drug targets that are both efficacious and safe to fill in the
critical unmet need of pharmaceutical therapy of obesity.
Terms: <Action Potentials><Adverse effects><Agonist><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Anxiety><Appetite><Arcuate Nucleus><BMI><BMI percentile><BMI z-score><Behavior><Behavioral><Bipolar Affective Psychosis><Bipolar Disorder><Blood Plasma><Body Weight decreased><Body fat><Body mass index><Brain><Brain Nervous System><Brain Stem><Brainstem><CNS Nervous System><CRISPR><CRISPR/Cas system><Caloric Intake><Candidate Disease Gene><Candidate Gene><Central Nervous System><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Data><Desire for food><Digestion><Dopamine Antagonists><Dopamine Receptor Antagonists><Dopaminergic Antagonists><Drug Targeting><Drug usage><Drugs><Eating><Electronic Health Record><Encephalon><Endocannabinoids><Endogenous Cannabinoids><Energy Intake><Esthesia><FDA approved><Feeling suicidal><Food Intake><GLP-1 receptor><GLP-I receptor><GWA study><GWAS><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetic study><Health system><Hypothalamic structure><Hypothalamus><In Vitro><Individual><Induced pluripotent stem cell derived neurons><Infundibular Nucleus><Insulinoma amyloid peptide><Intermediary Metabolism><Investigation><LEPR><LEPR gene><Length><Leptin><Limbic System><Link><Major Depressive Disorder><Manic-Depressive Psychosis><Medication><Mendelian randomization><Mental Depression><Metabolic Processes><Metabolism><Methodology><Molecular><Moods><Mutation><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neurites><Neurocyte><Neuron from iPSC><Neuron from induced pluripotent stem cells><Neurons><Neuropeptides><Nucleus Accumbens><Ob Gene Product><Ob Protein><Obese Gene Product><Obese Protein><Obesity><Obesity Epidemic><Obsessive-Compulsive Disorder><Obsessive-Compulsive Neurosis><Participant><Pathogenicity><Pathway interactions><Patients><Peripheral><Persons><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Physical activity><Plasma><Plasma Serum><Prevention><Production><Proteins><Proteome><Quetelet index><Receptor Protein><Reporting><Research Resources><Resources><Reticuloendothelial System, Serum, Plasma><Rewards><Risk Behaviors><Risky Behavior><Safety><Satiation><Sensation><Smoking><Structure of nucleus infundibularis hypothalami><Suicidal thoughts><TOPMed><Therapeutic><Trans-Omics for Precision Medicine><Transcript><Veterans><Waist-Hip Ratio><Weight Loss><Weight Reduction><Work><acomplia><adipogenesis><adiposity><adult adiposity><adult obesity><adults with obesity><amlintide><amygdaloid nuclear complex><amylin><analog><antagonism><antagonist><at risk behavior><bariatric surgery><biobank><biorepository><bipolar affective disorder><bipolar disease><bipolar illness><bipolar mood disorder><body weight loss><caloric dietary content><cardiometabolic><cardiometabolism><clinical depression><co-morbid><co-morbidity><cohort><comorbidity><corpulence><depression><diabetes associated peptide><differentiation of pluripotent stem cells><differentiation protocol><drinking><drug action><drug use><drug/agent><effective therapy><effective treatment><electronic health care record><electronic health medical record><electronic health plan record><electronic health registry><electronic medical health record><exome><exome sequencing><exome-seq><exomes><functional genomics><gastric banding><gastric bypass surgery><gene signatures><genetic resource><genetic signature><genome mutation><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><global gene expression><global transcription profile><glucagon-like peptide-1 receptor><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><hypothalamic><iPS neurons><iPSC derived-neurons><implantable gastric stimulation banding><induced human pluripotent stem cells><induced pluripotent stem cell neurons><innovate><innovation><innovative><insulin signaling><insulinoma amyloid polypeptide><islet amyloid polypeptide><lipid biosynthesis><lipogenesis><liraglutide><major depression><major depression disorder><manic depressive disorder><manic depressive illness><neural circuit><neural circuitry><neurocircuitry><neuronal><neurons derived from induced pluripotent stem cells><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><obesity intervention><obesity risk><obesity surgery><obesity therapy><obesity treatment><pancreatic amylin><pathway><pharmaceutical><pharmacologic><phenome><pluripotent stem cell differentiation><programs><receptor><rimonabant><risk for obesity><risk of obesity><satiety><screening><screenings><stomach stapling><substance use><substance using><success><suicidal ideation><suicidal thinking><suicide ideation><synaptic circuit><synaptic circuitry><therapeutic target><thoughts about suicide><trait><transcriptome><virtual><waist-to-hip ratio><weight loss surgery><whole genome association analysis><whole genome association studies><whole genome association study><wt-loss><zimulti>