Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus.
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.
Michaud
J L
JL
Research Center, Hôpital Sainte-Justine, 3175 Côte Sainte-Catherine, Montreal, Quebec, H3T 1C5, Canada. jmichaud@justine.umontreal.ca
Boucher
F
F
Melnyk
A
A
Gauthier
F
F
Goshu
E
E
Lévy
E
E
Mitchell
G A
GA
Himms-Hagen
J
J
Fan
C M
CM
D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001824:Body Constitution / Q000235:genetics; D005260:Female; D018257:Helix-Loop-Helix Motifs; D006579:Heterozygote; D006963:Hyperphagia / Q000235:genetics*; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000473:pathology; D009765:Obesity / Q000235:genetics*; D010286:Paraventricular Hypothalamic Nucleus / Q000002:abnormalities*; D012097:Repressor Proteins; D012737:Sex Factors; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D007328:Insulin; D012097:Repressor Proteins; D014157:Transcription Factors; C101750:Sim1 protein, mouse