Ablation of Sim1 Neurons Causes Obesity through Hyperphagia and Reduced Energy Expenditure

Abstract

Single-minded 1 (Sim1) is a transcription factor necessary for development of the paraventricular nucleus of the hypothalamus (PVH). This nucleus is a critical regulator of appetite, energy expenditure and body weight. Previously we showed that Sim1+/− mice and conditional postnatal Sim1−/− mice exhibit hyperphagia, obesity, increased linear growth and susceptibility to diet-induced obesity, but no decrease in energy expenditure. Bilateral ablation of the PVH causes obesity due to hyperphagia and reduced energy expenditure. It remains unknown whether Sim1 neurons regulate energy expenditure. In this study, Sim1cre mice were bred to homozygous inducible diphtheria toxin receptor (iDTR) mice to generate mice expressing the simian DTR in Sim1 cells. In these mice, Sim1 neuron ablation was performed by intracerebroventricular (ICV) injection of diphtheria toxin. Compared to controls, mice with Sim1 neuron ablation became obese (with increased fat mass) on a chow diet due to increased food intake and reduced energy expenditure. In post-injection mice, we observed a strong inverse correlation between the degree of obesity and hypothalamic Sim1 expression. The reduction in baseline energy expenditure observed in these mice was accompanied by a reduction in activity. This reduction in activity did not fully account for the reduced energy expenditure as these mice exhibited decreased resting energy expenditure, decreased body temperature, decreased brown adipose tissue temperature, and decreased UCP1 expression suggesting an impairment of thermogenesis. In injected mice, hypothalamic gene expression of Sim1, oxytocin (OXT) and thyrotropin releasing hormone (TRH) was reduced by about 50%. These results demonstrate that Sim1 neurons in adult mice regulate both food intake and energy expenditure. Based on the body of work in the field, feeding regulation by Sim1 neurons likely occurs in both the PVH and medial amygdala, in contrast to energy expenditure regulation by Sim1 neurons, which likely is localized to the PVH.

Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

“…46,47 Sim1 neuron ablation in adult mice induces hyperphagic obesity. 48 In humans, SIM1 disruption due to an apparently balanced translocation caused severe obesity and hyperphagia in a girl. 49 Obesity was a feature in several patients with 6q16 deletion and SIM1 deficiency (Figure 3 and Table 3).…”

Associations between oxytocin-related genes and autistic-like traits

“…This SNP was also nominally associated with total ASD scores and social interaction impairment. SIM1 has been previously studied for associations with obesity and hyperphagia, with a demonstrated lowering of hypothalamic oxytocin mRNA expression (Xi et al, 2012) and oxytocin peptide levels (Kublaoui et al, 2008) in SIM1 haploinsufficient mice.…”

“…It has so far been studied mainly with a focus on hyperphagia and obesity, with an effect demonstrated by mice haploinsufficient for the SIM1 gene (Xi et al, 2012). It has been shown that SIM1 is important for oxytocin expression in the PVN, with a near 80% reduction in haploinsufficient mice (Kublaoui et al, 2008).…”

Rare variants in single-minded 1 (SIM1) are associated with severe obesity

“…This implies that Mc4r and Sim1 are coexpressed in a subset of neurons and that Mc4r in these neurons is critical to the central melanocortin pathway, which influences body weight by modulating food intake independently of energy expenditure (37). However, targeted ablation of Sim1-expressing neurons with diphtheria toxin resulted in obesity resultant from both hyperphagia and reduced energy expenditure, suggesting additional Sim1 independent roles exist in at least some Sim1-expressing neurons to regulate energy balance (38).…”