Role of Hypothalamic Sim1 in Hyperphagic Obesity

Single-minded 1 (SIM1) mutations are one of the few known causes of monogenic obesity in both humans and mice. Sim1 encodes a transcription factor essential for formation of the hypothalamic paraventricular nucleus (PVN), and haploinsufficiency of mouse Sim1 causes hyperphagic obesity with increased linear growth and enhanced sensitivity to a high-fat diet. While the role for Sim1 in the formation of the hypothalamus has been described, its post-developmental, physiologic functions have not been well established. Here I present my work in elucidating the role of hypothalamic Sim1 in hyperphagic obesity. First, I show that overexpression of SIM1 in transgenic mice causes no obvious phenotype on a low-fat chow diet but confers resistance to diet-induced obesity on a high fat diet. I show this change to be due to reduced food intake with no change in energy expenditure. Additionally, the SIM1 transgene completely rescues the hyperphagia and partially rescues the obesity of agouti yellow mice, in which melanocortin signaling is abrogated. Next, I investigate the hypothesis that altered PVN neuropeptide expression mediates the hyperphagia of Sim1+/- mice. I show oxytocin (Oxt) mRNA and peptide are markedly decreased in Sim1+/- mice, and that Sim1+/- mice are hypersensitive to an Oxt receptor antagonist, while repeated Oxt injections decrease the food intake and weight gain of Sim1+/- mice. Finally, I demonstrate that postnatal CNS deficiency of Sim1 causes hyperphagic obesity by conditionally deleting Sim1 after birth. I also generate viable conditional Sim1 homozygotes, demonstrating that adult Sim1 expression is not essential for neuronal survival. Furthermore, I show that the phenotype of both conventional heterozygotes and conditional Sim1 homozygotes was not attributable to hypocellularity of the PVN or changes in projections to the hindbrain. My work indicates that Sim1 controls food intake but not energy expenditure, supports the importance of Oxt neurons in feeding regulation, suggests that reduced Oxt neuropeptide is one mechanism mediating the hyperphagic obesity of Sim1+/- mice, and demonstrates that Sim1’s role in feeding regulation is not limited to formation of the PVN. Collectively, these studies support a physiological role for Sim1 in hyperphagic obesity after the development of the PVN. [Keywords: single-minded 1 (Sim1); obesity; hyperphagia; hypothalamus; oxytocin; melanocortin 4 receptor (Mc4r); paraventricular nucleus (PVN); transcription factor]