Sim1 haploinsufficiency impairs melanocortin-mediated anorexia and activation of paraventricular nucleus neurons

Bassil M. Kublaoui, J. Lloyd Holder, Terry Gemelli, Andrew R. Zinn

Research output: Contribution to journalArticle

84 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2483-2492
Number of pages10
JournalMolecular Endocrinology
Volume20
Issue number10
DOIs
StatePublished - 2006

Fingerprint

Melanocortins
Haploinsufficiency
Paraventricular Hypothalamic Nucleus
Anorexia
Neurons
Receptor, Melanocortin, Type 4
Energy Metabolism
Obesity
Heterozygote
Pro-Opiomelanocortin
Hyperphagia
High Fat Diet
Leptin
Knockout Mice
Transcription Factors
Phenotype
Gene Expression
Growth
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Sim1 haploinsufficiency impairs melanocortin-mediated anorexia and activation of paraventricular nucleus neurons. / Kublaoui, Bassil M.; Holder, J. Lloyd; Gemelli, Terry; Zinn, Andrew R.

In: Molecular Endocrinology, Vol. 20, No. 10, 2006, p. 2483-2492.

Research output: Contribution to journalArticle

Kublaoui, Bassil M. ; Holder, J. Lloyd ; Gemelli, Terry ; Zinn, Andrew R. / Sim1 haploinsufficiency impairs melanocortin-mediated anorexia and activation of paraventricular nucleus neurons. In: Molecular Endocrinology. 2006 ; Vol. 20, No. 10. pp. 2483-2492.
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