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Hum Mol Genet ; 10(14): 1465-73, 2001 Jul 01.
Article in English | MEDLINE | ID: mdl-11448938

ABSTRACT

The bHLH-PAS transcription factor SIM1 is required for the development of the paraventricular nucleus (PVN) of the hypothalamus. Mice homozygous for a null allele of Sim1 (Sim1(-/-)) lack a PVN and die perinatally. In contrast, we show here that Sim1 heterozygous mice are viable but develop early-onset obesity, with increased linear growth, hyperinsulinemia and hyperleptinemia. Sim1(+/-) mice are hyperphagic but their energy expenditure is not decreased, distinguishing them from other mouse models of early-onset obesity such as deficiencies in leptin and melanocortin receptor 4. Quantitative histological comparison with normal littermates showed that the PVN of Sim1(+/-) mice contains on average 24% fewer cells without a selective loss of any identifiable major cell type. Since acquired lesions in the PVN also induce increased appetite without a decrease in energy expenditure, we propose that abnormalities of PVN development cause the obesity of Sim1(+/-) mice. Severe obesity was described recently in a patient with a balanced translocation disrupting SIM1. Pathways controlling the development of the PVN thus have the potential to cause obesity in both mice and humans.


Subject(s)
Hyperphagia/genetics , Obesity/genetics , Paraventricular Hypothalamic Nucleus/abnormalities , Repressor Proteins , Transcription Factors/physiology , Adipose Tissue/metabolism , Adipose Tissue/pathology , Adipose Tissue, Brown/cytology , Adipose Tissue, Brown/metabolism , Age Factors , Animals , Basic Helix-Loop-Helix Transcription Factors , Body Constitution/genetics , Female , Helix-Loop-Helix Motifs , Heterozygote , Insulin/blood , Male , Mice , Mice, Inbred Strains , Neurons/pathology , Sex Factors , Transcription Factors/genetics
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