Human Molecular Genetics

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Human Molecular Genetics, 2001, Vol. 10, No. 14 1465-1473
© 2001 Oxford University Press

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

Jacques L. Michaud⁺, Francine Boucher, Anna Melnyk¹, France Gauthier, Eleni Goshu², Emile Lévy, Grant A. Mitchell, Jean Himms-Hagen¹ and Chen-Ming Fan²

Research Center, Hôpital Sainte-Justine, 3175 Côte Sainte-Catherine, Montreal, Quebec, H3T 1C5, Canada, ¹Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada and ²Department of Embryology, Carnegie Institution of Washington, 115 West University Parkway, Baltimore, MD, USA

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.

⁺ To whom correspondence should be addressed. Tel: +1 514 345 4727; Fax: +1 514 345 4766; Email: jmichaud@justine.umontreal.ca

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