Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus

Hum Mol Genet. 2001 Jul 1;10(14):1465-73. doi: 10.1093/hmg/10.14.1465.


The bHLH-PAS transcription factor SIM1 is required for the development of the paraventricular nucleus (PVN) of the hypothalamus. Mice homozygous for a null allele of Sim1 (Sim1(-/-)) lack a PVN and die perinatally. In contrast, we show here that Sim1 heterozygous mice are viable but develop early-onset obesity, with increased linear growth, hyperinsulinemia and hyperleptinemia. Sim1(+/-) mice are hyperphagic but their energy expenditure is not decreased, distinguishing them from other mouse models of early-onset obesity such as deficiencies in leptin and melanocortin receptor 4. Quantitative histological comparison with normal littermates showed that the PVN of Sim1(+/-) mice contains on average 24% fewer cells without a selective loss of any identifiable major cell type. Since acquired lesions in the PVN also induce increased appetite without a decrease in energy expenditure, we propose that abnormalities of PVN development cause the obesity of Sim1(+/-) mice. Severe obesity was described recently in a patient with a balanced translocation disrupting SIM1. Pathways controlling the development of the PVN thus have the potential to cause obesity in both mice and humans.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adipose Tissue / metabolism
  • Adipose Tissue / pathology
  • Adipose Tissue, Brown / cytology
  • Adipose Tissue, Brown / metabolism
  • Age Factors
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Body Constitution / genetics
  • Female
  • Helix-Loop-Helix Motifs
  • Heterozygote
  • Hyperphagia / genetics*
  • Insulin / blood
  • Male
  • Mice
  • Mice, Inbred Strains
  • Neurons / pathology
  • Obesity / genetics*
  • Paraventricular Hypothalamic Nucleus / abnormalities*
  • Repressor Proteins*
  • Sex Factors
  • Transcription Factors / genetics
  • Transcription Factors / physiology*


  • Basic Helix-Loop-Helix Transcription Factors
  • Insulin
  • Repressor Proteins
  • Sim1 protein, mouse
  • Transcription Factors