title: Sim1 haploinsufficiency impairs melanocortin-mediated anorexia and activation of paraventricular nucleus neurons.
abstract: Single-minded 1 (SIM1) is one of only six genes implicated in human monogenic obesity. Haploinsufficiency of this hypothalamic transcription factor is associated with hyperphagic obesity and increased linear growth in both humans and mice. Additionally, Sim1 heterozygous mice show enhanced hyperphagia and obesity in response to a high-fat diet. Thus the phenotype of Sim1 haploinsufficiency is similar to that of agouti yellow (Ay), and melanocortin 4 receptor (Mc4r) knockout mice, both of which are defective in hypothalamic melanocortin signaling. Sim1 and Mc4r are both expressed in the paraventricular nucleus (PVN). Here we report that Sim1 heterozygous mice, which have normal energy expenditure, are hyperphagic despite having elevated hypothalamic proopiomelanocortin (Pomc) expression. In response to the melanocortin agonist melanotan-2 (MTII) they exhibit a blunted suppression of feeding yet increase their energy expenditure normally. They also fail to activate PVN neurons in response to the drug at a dose that induces robust c-Fos expression in a subset of Sim1 PVN neurons in wild-type mice. The resistance to melanocortin signaling in Sim1 heterozygotes is not due to a reduced number of Sim1 neurons in the PVN. Hypothalamic Sim1 gene expression is induced by leptin and MTII treatment. Our results demonstrate that Sim1 heterozygotes are resistant to hypothalamic melanocortin signaling and suggest that Sim1-expressing PVN neurons regulate feeding, but not energy expenditure, in response to melanocortin signaling.
authors.affiliation: Department of Pediatrics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8591, USA. bassil.kublaoui@utsouthwestern.edu
authors.forename: Bassil M
authors.initials: BM
authors.lastname: Kublaoui
authors.forename: J Lloyd
authors.initials: JL
authors.lastname: Holder
authors.forename: Terry
authors.initials: T
authors.lastname: Gemelli
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Zinn
mesh_terms: D000818:Animals; D000855:Anorexia / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006579:Heterozygote; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011333:Pro-Opiomelanocortin / Q000819:agonists / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017931:DNA Primers; D010456:Peptides, Cyclic; D011333:Pro-Opiomelanocortin; D012097:Repressor Proteins; D000521:alpha-MSH; C101750:Sim1 protein, mouse; C079282:melanotan-II