The bHLH/PAS Transcription Factor SIM1 Is a Novel Obesity Gene

Obesity is epidemic in the United States and other developed countries. Obesity is a major risk factor for type II diabetes, hypertension, hyperlipidemia and osteoarthritis. I report a unique girl with early-onset obesity (47.5 kg, +9.3 s.d. above mean at age 67 months) and a de novo balanced translocation between chromosomes 1 and 6. She has normal energy expenditure and a voracious appetite. I show that her translocation disrupts a transcription factor gene, SIM1, on chromosome 6q16.2. I also present data that Sim1 haploinsufficiency causes obesity in mice. Animals heterozygous for a Sim1 null allele fed a standard chow diet (4% fat) developed obesity around the time of sexual maturity, were 33-45% heavier than wild-type littermates by 5 months of age, and had increased adiposity by DEXA scans. In contrast, the human subject developed obesity by two years of age, well before puberty. To investigate whether differences in dietary fat consumption might explain this discrepancy in human and mouse phenotypes, I fed mutant mice and wild type littermates a "Westernized" diet (35% fat). Heterozygous Sim1 mice fed this diet became obese prior to 6 weeks of age. The obesity was also more severe, especially in females, who by 8 weeks of age weighed 72% more than controls compared with 13% on a low fat diet. Heterozygous Sim1 mice maintained on a 4% fat diet ate more than controls over a 5 day period (delta kcals 12-14%), and became even more hyperphagic when acutely challenged with increased dietary fat (delta kcals 46-68% over 5 days). This altered behavior was evident within the first day of exposure to the high fat diet: during this time, heterozygous Sim1 mice failed to significantly change the mass of food consumed, whereas wild-type littermates decreased their food consumption by >15%. These data suggest that Sim1 is critical for the acute and chronic homeostatic response to elevated dietary fat. This data demonstrates that normal Sim1 gene dosage is critical for proper regulation of feeding behavior and body weight regulation.