Document Detail


Critical role of the Src homology 2 (SH2) domain of neuronal SH2B1 in the regulation of body weight and glucose homeostasis in mice.
MedLine Citation:
PMID:  20484460     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
SH2B1 is an SH2 domain-containing adaptor protein that plays a key role in the regulation of energy and glucose metabolism in both rodents and humans. Genetic deletion of SH2B1 in mice results in obesity and type 2 diabetes. Single-nucleotide polymorphisms in the SH2B1 loci and chromosomal deletions of the SH2B1 loci associate with obesity and insulin resistance in humans. In cultured cells, SH2B1 promotes leptin and insulin signaling by binding via its SH2 domain to phosphorylated tyrosines in Janus kinase 2 and the insulin receptor, respectively. Here we generated three lines of mice to analyze the role of the SH2 domain of SH2B1 in the central nervous system. Transgenic mice expressing wild-type, SH2 domain-defective (R555E), or SH2 domain-alone (DeltaN503) forms of SH2B1 specifically in neurons were crossed with SH2B1 knockout mice to generate KO/SH2B1, KO/R555E, or KO/DeltaN503 compound mutant mice. R555E had a replacement of Arg(555) with Glu within the SH2 domain. DeltaN503 contained an intact SH2 domain but lacked amino acids 1-503. Neuron-specific expression of recombinant SH2B1, but not R555E or DeltaN503, corrected hyperphagia, obesity, glucose intolerance, and insulin resistance in SH2B1 null mice. Neuron-specific expression of R555E in wild-type mice promoted obesity and insulin resistance. These results indicate that in addition to the SH2 domain, N-terminal regions of neuronal SH2B1 are also required for the maintenance of normal body weight and glucose metabolism. Additionally, mutations in the SH2 domain of SH2B1 may increase the susceptibility to obesity and type 2 diabetes in a dominant-negative manner.
Authors:
David L Morris; Kae Won Cho; Liangyou Rui
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-05-19
Journal Detail:
Title:  Endocrinology     Volume:  151     ISSN:  1945-7170     ISO Abbreviation:  Endocrinology     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-07-27     Completed Date:  2010-09-08     Revised Date:  2014-04-03    
Medline Journal Info:
Nlm Unique ID:  0375040     Medline TA:  Endocrinology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3643-51     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / chemistry,  genetics,  metabolism,  physiology*
Animals
Body Weight / genetics*
Central Nervous System / metabolism
Diabetes Mellitus, Type 2 / genetics
Energy Metabolism / genetics
Genetic Predisposition to Disease
Glucose / metabolism*
Homeostasis / genetics*,  physiology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutant Proteins / genetics,  metabolism
Mutation / physiology
Neurons / metabolism
Obesity / genetics
Organ Specificity / genetics
Protein Isoforms / genetics
src Homology Domains / genetics,  physiology*
Grant Support
ID/Acronym/Agency:
5 P30 CA46592/CA/NCI NIH HHS; 5P60DK20572/DK/NIDDK NIH HHS; DK34933/DK/NIDDK NIH HHS; F31 NS056575/NS/NINDS NIH HHS; F31 NS056575-03/NS/NINDS NIH HHS; F31NS056575/NS/NINDS NIH HHS; P30AG013283/AG/NIA NIH HHS; R01 DK 065122/DK/NIDDK NIH HHS; R01 DK065122/DK/NIDDK NIH HHS; R01 DK073601/DK/NIDDK NIH HHS; R01 DK073601/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Mutant Proteins; 0/Protein Isoforms; 0/Sh2bpsm1 protein, mouse; IY9XDZ35W2/Glucose
Comments/Corrections
Comment In:
Endocrinology. 2010 Sep;151(9):4100-2   [PMID:  20736406 ]

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