SIM1 and SIM2 genes are homologs of Drosophila melanogaster single-minded (sim), so named because cells in the midline of the sim mutant embryo fail to properly develop and eventually die, and thus the paired longitudinal axon bundles that span the anterior-posterior axis of the embryo (analogous to the embryo's spinal cord) are collapsed into a "single" rudimentary axon bundle at the midline. Sim is a basic helix-loop-helix-PAS domaintranscription factor that regulates gene expression in the midline cells. Since the sim gene plays an important role in Drosophila development and has peak levels of expression during the period of neurogenesis, it was proposed that the human SIM2 gene, which resides in a critical region of chromosome 21, is a candidate for involvement in certain dysmorphic features (particularly facial and skull characteristics), abnormalities of brain development, and/or mental retardation of Down syndrome.
Haploinsufficiency of SIM1 has been shown to cause severe early-onset obesity in a human girl with a de novo balanced translocation between chromosomes 1p22.1 and 6q16.2  and has been suggested to cause a Prader-Willi-like phenotype in other cases. Additionally, studies in mice have shown that haploinsufficieny of Sim1 causes obesity that is due to hyperphagia and do not respond properly to increased dietary fat. Overexpression of SIM1 protects against diet induced obesity and rescues the hyperphagia of agouti yellow mice, who have disrupted melanocortin signaling. The obesity and hyperphagia may be mediated by impaired melanocortin activation of PVN neurons  and oxytocin deficiency in these mice. It has been demonstrated that modulating Sim1 levels postnatally also leads to hyperphagia and obesity, suggesting a physiological role for Sim1 separate from its role in development.
^ abMichaud JL, Boucher F, Melnyk A, Gauthier F, Goshu E, Levy E, Mitchell GA, Himms-Hagen J, Fan CM (July 2001). "Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus". Hum Mol Genet10 (14): 1465–73. doi:10.1093/hmg/10.14.1465. PMID11448938.
^Yang C, Gagnon D, Vachon P, Tremblay A, Levy E, Massie B, Michaud JL (June 2006). "Adenoviral-mediated modulation of Sim1 expression in the paraventricular nucleus affects food intake". J Neurosci26 (26): 7116–20. doi:10.1523/JNEUROSCI.0672-06.2006. PMID16807340.
^Probst, M R; Fan C M, Tessier-Lavigne M, Hankinson O (February 1997). "Two murine homologs of the Drosophila single-minded protein that interact with the mouse aryl hydrocarbon receptor nuclear translocator protein". J. Biol. Chem. (UNITED STATES) 272 (7): 4451–7. doi:10.1074/jbc.272.7.4451. ISSN0021-9258. PMID9020169.Cite uses deprecated parameters (help)
^Woods, Susan L; Whitelaw Murray L (March 2002). "Differential activities of murine single minded 1 (SIM1) and SIM2 on a hypoxic response element. Cross-talk between basic helix-loop-helix/per-Arnt-Sim homology transcription factors". J. Biol. Chem. (United States) 277 (12): 10236–43. doi:10.1074/jbc.M110752200. ISSN0021-9258. PMID11782478.Cite uses deprecated parameters (help)
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Probst MR, Fan CM, Tessier-Lavigne M, Hankinson O (1997). "Two murine homologs of the Drosophila single-minded protein that interact with the mouse aryl hydrocarbon receptor nuclear translocator protein.". J. Biol. Chem.272 (7): 4451–7. doi:10.1074/jbc.272.7.4451. PMID9020169.
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Woods SL, Whitelaw ML (2002). "Differential activities of murine single minded 1 (SIM1) and SIM2 on a hypoxic response element. Cross-talk between basic helix-loop-helix/per-Arnt-Sim homology transcription factors.". J. Biol. Chem.277 (12): 10236–43. doi:10.1074/jbc.M110752200. PMID11782478.
Yamaki A, Kudoh J, Shimizu N, Shimizu Y (2004). "A novel nuclear localization signal in the human single-minded proteins SIM1 and SIM2.". Biochem. Biophys. Res. Commun.313 (3): 482–8. doi:10.1016/j.bbrc.2003.11.168. PMID14697214.
Meyre D, Lecoeur C, Delplanque J, et al. (2004). "A genome-wide scan for childhood obesity-associated traits in French families shows significant linkage on chromosome 6q22.31-q23.2.". Diabetes53 (3): 803–11. doi:10.2337/diabetes.53.3.803. PMID14988267.
Kublaoui BM, Holder JL, Tolson KP, et al. (2006). "SIM1 overexpression partially rescues agouti yellow and diet-induced obesity by normalizing food intake.". Endocrinology147 (10): 4542–9. doi:10.1210/en.2006-0453. PMID16709610.