Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice

Bassil M. Kublaoui, Terry Gemelli, Kristen P. Tolson, Yu Wang, Andrew R. Zinn

Research output: Contribution to journalArticle

146 Citations (Scopus)

Abstract

Single-minded 1 (Sim1) encodes a transcription factor essential for formation of the hypothalamic paraventricular nucleus (PVN). Sim1 haploinsufficiency is associated with hyperphagic obesity and increased linear growth in humans and mice, similar to the phenotype of melanocortin 4 receptor (Mc4r) mutations. PVN neurons in Sim1+/- mice are hyporesponsive to the melanocortin agonist melanotan II. PVN neuropeptides oxytocin (Oxt), TRH and CRH inhibit feeding when administered centrally. Consequently, we hypothesized that altered PVN neuropeptide expression mediates the hyperphagia of Sim1 +/- mice. To test this hypothesis, we measured hypothalamic expression of PVN neuropeptides in Sim1+/- and wild-type mice. Oxt mRNA and peptide were decreased by 80% in Sim1+/- mice, whereas TRH, CRH, arginine vasopressin (Avp), and somatostatin mRNAs were decreased by 20-40%. Sim1+/- mice also showed abnormal regulation of Oxt but not CRH mRNA in response to feeding state. A selective Mc4r agonist activated PVN Oxt neurons in wild-type mice, supporting involvement of these neurons in melanocortin feeding circuits. To test whether Oxt itself regulates feeding, we measured the effects of central administration of an Oxt receptor antagonist or repeated doses of Oxt on food intake of Sim1+/- and wild-type mice. Sim1+/- mice were hypersensitive to the orexigenic effect of the Oxt receptor antagonist. Oxt decreased the food intake and weight gain of Sim1 +/- mice at a dose that did not affect wild-type mice. Our results support the importance of Oxt neurons in feeding regulation and suggest that reduced Oxt neuropeptide is one mechanism mediating the hyperphagic obesity of Sim1+/- mice.

Original languageEnglish (US)
Pages (from-to)1723-1734
Number of pages12
JournalMolecular Endocrinology
Volume22
Issue number7
DOIs
StatePublished - Jul 2008

Fingerprint

Oxytocin
Obesity
Paraventricular Hypothalamic Nucleus
Neuropeptides
Receptor, Melanocortin, Type 4
Melanocortins
Oxytocin Receptors
Neurons
Messenger RNA
Eating
Haploinsufficiency
Hyperphagia
Arginine Vasopressin
Somatostatin
Weight Gain
Transcription Factors
Phenotype

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice. / Kublaoui, Bassil M.; Gemelli, Terry; Tolson, Kristen P.; Wang, Yu; Zinn, Andrew R.

In: Molecular Endocrinology, Vol. 22, No. 7, 07.2008, p. 1723-1734.

Research output: Contribution to journalArticle

Kublaoui, Bassil M. ; Gemelli, Terry ; Tolson, Kristen P. ; Wang, Yu ; Zinn, Andrew R. / Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice. In: Molecular Endocrinology. 2008 ; Vol. 22, No. 7. pp. 1723-1734.
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