Postnatal Sim1 deficiency causes hyperphagic obesity and reduced Mc4r and oxytocin expression

Kristen P. Tolson, Terry Gemelli, Laurent Gautron, Joel K. Elmquist, Andrew R. Zinn, Bassil M. Kublaoui

Research output: Contribution to journalArticlepeer-review

108 Scopus citations


Single-minded 1 (SIM1) mutations are one of the few known causes of nonsyndromic monogenic obesity in both humans and mice. Although the role of Sim1 in the formation of the hypothalamus has been described, its postdevelopmental, physiological functions have not been well established. Here we demonstrate that postnatal CNS deficiency of Sim1 is sufficient to cause hyperphagic obesity. We conditionally deleted Sim1 after birth using CaMKII-Cre (α-calcium/calmodulin-dependent protein kinase II-Cre) lines to recombine a floxed Sim1 allele. Conditional Sim1 heterozygotes phenocopied germ line Sim1 heterozygotes, displaying hyperphagic obesity and increased length. We also generated viable conditional Sim1 homozygotes, demonstrating that adult Sim1 expression is not essential for mouse or neuron survival and revealing a dosage-dependent effect of Sim1 on obesity. Using stereological cell counting, we showed that the phenotype of both germ line heterozygotes and conditional Sim1 homozygotes was not attributable to global hypocellularity of the paraventricular nucleus (PVN) of the hypothalamus. We also used retrograde tract tracing to demonstrate that the PVN of germ line heterozygous mice projects normally to the dorsal vagal complex and the median eminence. Finally, we showed that conditional Sim1 homozygotes and germ line Sim1 heterozygotes exhibit a remarkable decrease in hypothalamic oxytocin (Oxt) and PVN melanocortin 4 receptor (Mc4r) mRNA. These results demonstrate that the role of Sim1 in feeding regulation is not limited to formation of the PVN or its projections and that the hyperphagic obesity in Sim1-deficient mice may be attributable to changes in the leptin-melanocortin- oxytocin pathway.

Original languageEnglish (US)
Pages (from-to)3803-3812
Number of pages10
JournalJournal of Neuroscience
Issue number10
StatePublished - Mar 10 2010

ASJC Scopus subject areas

  • Neuroscience(all)


Dive into the research topics of 'Postnatal Sim1 deficiency causes hyperphagic obesity and reduced Mc4r and oxytocin expression'. Together they form a unique fingerprint.

Cite this