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Your search keyword '"Garg, Sumedha"' showing total 2 results
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2 results on '"Garg, Sumedha"'

1. KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation

Author

Pearce, Laura R, Atanassova, Neli, Banton, Matthew C, Bottomley, Bill, van der Klaauw, Agatha A, Revelli, Jean-Pierre, Hendricks, Audrey, Keogh, Julia M, Henning, Elana, Doree, Deon, Jeter-Jones, Sabrina, Garg, Sumedha, Bochukova, Elena G, Bounds, Rebecca, Ashford, Sofie, Gayton, Emma, Hindmarsh, Peter C, Shield, Julian PH, Crowne, Elizabeth, Barford, David, Wareham, Nick J, UK10K consortium, O'Rahilly, Stephen, Murphy, Michael P, Powell, David R, Barroso, Ines, Farooqi, I Sadaf, Keogh, Julia [0000-0002-0399-4114], Henning, Elana [0000-0002-0399-4114], Wareham, Nicholas [0000-0003-1422-2993], O'Rahilly, Stephen [0000-0003-2199-4449], Murphy, Mike [0000-0003-1115-9618], Barroso, Ines [0000-0001-5800-4520], Farooqi, Ismaa [0000-0001-7609-3504], and Apollo - University of Cambridge Repository

Subjects
Male, Models, Molecular, Proto-Oncogene Proteins B-raf, MAP Kinase Signaling System, Fatty Acids, Molecular Sequence Data, Age Factors, Hyperphagia, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Mice, Glucose, Animals, Humans, Female, Amino Acid Sequence, Obesity, Age of Onset, Insulin Resistance, Child, Energy Metabolism, Oxidation-Reduction, Sequence Alignment
Abstract

Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.

Published
2013

2. Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity.

Author

Wheeler, Eleanor, Huang, Ni, Bochukova, Elena G, Keogh, Julia M, Lindsay, Sarah, Garg, Sumedha, Henning, Elana, Blackburn, Hannah, Loos, Ruth J F, Wareham, Nick J, O'Rahilly, Stephen, Hurles, Matthew E, Barroso, Inês, and Farooqi, I Sadaf

Subjects
SINGLE nucleotide polymorphisms, OBESITY, AGE of onset, BODY mass index, PLOIDY, GENE regulatory networks, G protein coupled receptors
Abstract

Common and rare variants associated with body mass index (BMI) and obesity account for <5% of the variance in BMI. We performed SNP and copy number variation (CNV) association analyses in 1,509 children with obesity at the extreme tail (>3 s.d. from the mean) of the BMI distribution and 5,380 controls. Evaluation of 29 SNPs (P < 1 × 10−5) in an additional 971 severely obese children and 1,990 controls identified 4 new loci associated with severe obesity (LEPR, PRKCH, PACS1 and RMST). A previously reported 43-kb deletion at the NEGR1 locus was significantly associated with severe obesity (P = 6.6 × 10−7). However, this signal was entirely driven by a flanking 8-kb deletion; absence of this deletion increased risk for obesity (P = 6.1 × 10−11). We found a significant burden of rare, single CNVs in severely obese cases (P < 0.0001). Integrative gene network pathway analysis of rare deletions indicated enrichment of genes affecting G protein-coupled receptors (GPCRs) involved in the neuronal regulation of energy homeostasis. [ABSTRACT FROM AUTHOR]

Published
2013
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