SIM1 overexpression partially rescues agouti yellow and diet-induced obesity by normalizing food intake.
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.
Kublaoui
Bassil M
BM
Department of Pediatrics, and McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, 75390-8591, USA. bassil.kublaoui@utsouthwestern.edu
Holder
J Lloyd
JL
Tolson
Kristen P
KP
Gemelli
Terry
T
Zinn
Andrew R
AR
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000502:physiology*; D001823:Body Composition / Q000502:physiology; D004032:Diet; D004435:Eating / Q000235:genetics* / Q000502:physiology*; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D005260:Female; D005838:Genotype; D006128:Growth / Q000235:genetics / Q000502:physiology; D006801:Humans; D006963:Hyperphagia / Q000235:genetics / Q000523:psychology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000502:physiology; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes; D000521:alpha-MSH / Q000502:physiology
D051792:Basic Helix-Loop-Helix Proteins; D011333:Pro-Opiomelanocortin; D044105:Receptor, Melanocortin, Type 4; D012097:Repressor Proteins; D000521:alpha-MSH; C470072:MC4R protein, human; C491094:SIM1 protein, human