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Submitted on April 10, 2006
Accepted on May 10, 2006
Department of Pediatrics, Department of Internal Medicine McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75390-8591
* To whom correspondence should be addressed. E-mail: bassil.kublaoui{at}utsouthwestern.edu.
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 (Ay) and melanocortin 4 receptor (Mc4r) 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 Ay mice, in which melanocortin signaling is abrogated. Our results indicate that the Mc4r signals through Sim1 or its transcriptional targets in controlling food intake but not energy expenditure.
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