Inducible neuronal inactivation of Sim1 in adult mice causes hyperphagic obesity

Endocrinology. 2014 Jul;155(7):2436-44. doi: 10.1210/en.2013-2125. Epub 2014 Apr 28.


Germline haploinsufficiency of human or mouse Sim1 is associated with hyperphagic obesity. Sim1 encodes a transcription factor required for proper formation of the paraventricular (PVN), supraoptic, and anterior periventricular hypothalamic nuclei. Sim1 expression persists in these neurons in adult mice, raising the question of whether it plays a physiologic role in regulation of energy balance. We previously showed that Sim1 heterozygous mice had normal numbers of PVN neurons that were hyporesponsive to melanocortin 4 receptor agonism and showed reduced oxytocin expression. Furthermore, conditional postnatal neuronal inactivation of Sim1 also caused hyperphagic obesity and decreased hypothalamic oxytocin expression. PVN projections to the hindbrain, where oxytocin is thought to act to modulate satiety, were anatomically intact in both Sim1 heterozygous and conditional knockout mice. These experiments provided evidence that Sim1 functions in energy balance apart from its role in hypothalamic development but did not rule out effects of Sim1 deficiency on postnatal hypothalamic maturation. To address this possibility, we used a tamoxifen-inducible, neural-specific Cre transgene to conditionally inactivate Sim1 in adult mice with mature hypothalamic circuitry. Induced Sim1 inactivation caused increased food and water intake and decreased expression of PVN neuropeptides, especially oxytocin and vasopressin, with no change in energy expenditure. Sim1 expression was not required for survival of PVN neurons. The results corroborate previous evidence that Sim1 acts physiologically as well as developmentally to regulate body weight. Inducible knockout mice provide a system for studying Sim1's physiologic function in energy balance and identifying its relevant transcriptional targets in the hypothalamus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Body Weight / drug effects
  • Bone Density Conservation Agents / pharmacology
  • Eating / drug effects
  • Energy Metabolism / drug effects
  • Female
  • Homeostasis / drug effects
  • Hyperphagia / metabolism*
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neurons / metabolism*
  • Neuropeptides / metabolism
  • Obesity / metabolism*
  • Oxytocin / metabolism
  • Paraventricular Hypothalamic Nucleus / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Tamoxifen / pharmacology


  • Basic Helix-Loop-Helix Transcription Factors
  • Bone Density Conservation Agents
  • Neuropeptides
  • Repressor Proteins
  • Sim1 protein, mouse
  • Tamoxifen
  • Oxytocin