ablation of sim1 neurons causes obesity through hyperphagia and reduced energy expenditure消融sim1神经元通过摄食过量导致肥胖和降低能量消耗.pdfVIP

Ablation of Sim1 Neurons Causes Obesity through Hyperphagia and Reduced Energy Expenditure Dong Xi, Nilay Gandhi, Meizan Lai, Bassil M. Kublaoui* Division of Endocrinology and Diabetes, Department of Pediatrics, School of Medicine, The Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America 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+/ 2 mice and conditional postnatal Sim12/ 2 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 energ