Obesity is an extremely costly health problem, largely unresponsive to current therapeutic and prophylactic measures. Heritability estimates indicate that 30-50% of the likelihood of becoming obese is conveyed by genes, and over 100 genes leading to susceptibility to obesity have been identified in rodents and humans. However, the genes so far identified in the aggregate account for no more than ~5% of this risk. Genome wide association studies for obesity are inherently designed to detect common alleles present in 5% or more of the population. We hypothesize that some or most of the ?missing heritability? for obesity is due to rare variants.
In Aim 1 we will sequence the exomes (and possibly entire genomes) of individuals and their families in which severe, early-onset obesity is segregating. Multi-tiered bioinformatics filters and pathway analysis will be used to examine the biological functions, molecular networks, and canonical energy homeostasis pathways represented by the prioritized novel variants.
In Aim 2 ?the implicated genes will be characterized in: 1. hypothalamic neurons (and possibly other cell types) created from somatic cells of affected individuals as compared to their isogenic controls (generated using CRISPR); 2. Mice manipulated by direct injection of candidate gene constructs into the brain and mice segregating for knock-in alleles of the candidate gene. These animals will be studied using sophisticated measures of energy homeostasis and food intake, including studies of hedonic aspects of the quantity and quality of good intake. The stem cell-derived neurons will enable study of the developmental, structural, cellular, biochemical/molecular and functional phenotypes of not otherwise accessible for this type of analysis. Success in generating patient-specific hypothalamic neurons from human iPSCs will create a cellular ?reagent? likely to be extremely useful in molecular physiology and drug discovery. The combining of three elements of analysis: exome sequencing/pathway analysis, iPSC- derived hypothalamic neurons/other cells, and creation of animal models subjected to sophisticated metabolic and behavioral phenotyping provides a powerful platform for the identification of novel molecular mechanisms for human obesity. .

Public Health Relevance

By virtue of its impact on diabetes, cardiovascular disease, cancer and probably neurodegenerative disease, obesity is arguably the greatest single threat to health (and healthcare costs) in the U.S. today. Effective interventions are not available. The approaches proposed here, by elucidating the basic biology of weight regulation, will point to means of prevention and treatment. .

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052431-25
Application #
10000072
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Karp, Robert W
Project Start
1996-07-15
Project End
2021-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
25
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pediatrics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Stratigopoulos, George; De Rosa, Maria Caterina; LeDuc, Charles A et al. (2018) DMSO increases efficiency of genome editing at two non-coding loci. PLoS One 13:e0198637
Wang, Liheng; Sui, Lina; Panigrahi, Sunil K et al. (2017) PC1/3 Deficiency Impacts Pro-opiomelanocortin Processing in Human Embryonic Stem Cell-Derived Hypothalamic Neurons. Stem Cell Reports 8:264-277
Schwartz, Michael W; Seeley, Randy J; Zeltser, Lori M et al. (2017) Obesity Pathogenesis: An Endocrine Society Scientific Statement. Endocr Rev 38:267-296
Burnett, Lisa C; LeDuc, Charles A; Sulsona, Carlos R et al. (2017) Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome. J Clin Invest 127:293-305
Burnett, Lisa Cole; Hubner, Gabriela; LeDuc, Charles A et al. (2017) Loss of the imprinted, non-coding Snord116 gene cluster in the interval deleted in the Prader Willi syndrome results in murine neuronal and endocrine pancreatic developmental phenotypes. Hum Mol Genet 26:4606-4616
Morabito, Michael V; Ravussin, Yann; Mueller, Bridget R et al. (2017) Weight Perturbation Alters Leptin Signal Transduction in a Region-Specific Manner throughout the Brain. PLoS One 12:e0168226
Mosialou, Ioanna; Shikhel, Steven; Liu, Jian-Min et al. (2017) MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature 543:385-390
Burnett, L C; Skowronski, A A; Rausch, R et al. (2017) Determination of the half-life of circulating leptin in the mouse. Int J Obes (Lond) 41:355-359
Webster, Emily; Cho, Megan T; Alexander, Nora et al. (2016) De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features. Cold Spring Harb Mol Case Stud 2:a001172
Wang, Liheng; Egli, Dieter; Leibel, Rudolph L (2016) Efficient Generation of Hypothalamic Neurons from Human Pluripotent Stem Cells. Curr Protoc Hum Genet 90:21.5.1-21.5.14

Showing the most recent 10 out of 105 publications