Abstract
Single-minded 1 (SIM1) mutations are associated with obesity in mice and humans. Haploinsufficiency of mouse Sim1 causes hyperphagic obesity with increased linear growth and enhanced sensitivity to a high-fat diet, a phenotype similar to that of agouti yellow and melanocortin 4 receptor knockout mice. To investigate the effects of increased Sim1 dosage, we generated transgenic mice that overexpress human SIM1 and examined their phenotype. Compared with wild-type mice, SIM1 transgenic mice had no obvious phenotype on a low-fat chow diet but were resistant to diet-induced obesity on a high-fat diet due to reduced food intake with no change in energy expenditure. The SIM1 transgene also completely rescued the hyperphagia and partially rescued the obesity of agouti yellow mice, in which melanocortin signaling is abrogated. Our results indicate that the melanocortin 4 receptor signals through Sim1 or its transcriptional targets in controlling food intake but not energy expenditure.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics*
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Basic Helix-Loop-Helix Transcription Factors / physiology*
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Body Composition / physiology
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Diet
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Eating / genetics*
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Eating / physiology*
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Energy Metabolism / genetics
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Energy Metabolism / physiology
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Female
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Genotype
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Growth / genetics
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Growth / physiology
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Humans
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Hyperphagia / genetics
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Hyperphagia / psychology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Obesity / genetics*
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Pro-Opiomelanocortin / genetics
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Pro-Opiomelanocortin / physiology
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Receptor, Melanocortin, Type 4 / genetics
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Receptor, Melanocortin, Type 4 / physiology
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Repressor Proteins / genetics*
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Repressor Proteins / physiology*
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Reverse Transcriptase Polymerase Chain Reaction
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Transgenes
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alpha-MSH / physiology
Substances
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Basic Helix-Loop-Helix Transcription Factors
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MC4R protein, human
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Receptor, Melanocortin, Type 4
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Repressor Proteins
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SIM1 protein, human
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alpha-MSH
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Pro-Opiomelanocortin