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 t he paraventricular nucleus (PVN) of the hypothalamus. Mice homozygous for a null allele of Sim1 (Sim1(-/-)) lack a PVN and die perinatally. In contras t, we show here that Sim1 heterozygous mice are viable but develop early-on set obesity, with increased linear growth, hyperinsulinemia and hyperleptin emia. Sim1(+/-) mice are hyperphagic but their energy expenditure is not de creased, distinguishing them from other mouse models of early-onset obesity such as deficiencies in leptin and melanocortin receptor 4. Quantitative h istological comparison with normal littermates showed that the PVN of Sim1( +/-) mice contains on average 24% fewer cells without a selective loss of a ny identifiable major cell type. Since acquired lesions in the PVN also ind uce 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 translo cation disrupting SIM1. Pathways controlling the development of the PVN thu s have the potential to cause obesity in both mice and humans.