title: Paraventricular nucleus Sim1 neuron ablation mediated obesity is resistant to high fat diet.
abstract: Single minded 1 (SIM1) is a transcription factor involved in brain patterning and control of energy balance. In humans, haploinsufficiency of SIM1 causes early-onset obesity. Mice deficient in the homologous gene, SIM1, also exhibit early onset obesity and increased sensitivity to a high fat diet. SIM1 is expressed in several areas of the brain implicated in control of energy balance including the paraventricular nucleus (PVN), the supraoptic nucleus (SON), the medial amygdala and nucleus of the lateral olfactory tract. We have previously shown that mice with global Sim1 neuron ablation exhibit obesity with hyperphagia as the primary defect. The PVN has a critical role in feeding and in high-fat appetite, thus, we sought to determine the effect of Sim1 neuron ablation limited to the PVN. We achieved PVN-SIM1 limited ablation through stereotactic injection of diphtheria toxin into the PVN of Sim1Cre-iDTR mice. The specificity of this ablation was confirmed by immunohistochemistry and quantitative real time PCR of the PVN, supraoptic nucleus and the amygdala. Mice with PVN Sim1 neuron ablation, similar to mice with global Sim1 neuron ablation, exhibit early onset obesity with hyperphagia as the primary defect. However, PVN-Sim1 neuron ablated mice have a decreased response to fasting-induced hyperphagia. Consistent with this decrement, PVN-Sim1 neuron ablated mice have a decreased hyperphagic response to PVN injection of agouti-related peptide (AgRP). When PVN-Sim1 neuron ablated mice are placed on a high fat diet, surprisingly, their intake decreases and they actually lose weight. When allowed ad lib access to high fat diet and normal chow simultaneously, PVN-Sim1 neuron ablated mice exhibit overall decreased intake. That is, in PVN-Sim1 neuron ablated mice, access to fat suppresses overall appetite.
authors.affiliation: Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Dong
authors.initials: D
authors.lastname: Xi
authors.forename: Jeff
authors.initials: J
authors.lastname: Roizen
authors.forename: Meizan
authors.initials: M
authors.lastname: Lai
authors.forename: Nilay
authors.initials: N
authors.lastname: Gandhi
authors.forename: Bassil
authors.initials: B
authors.lastname: Kublaoui
mesh_terms: D054369:Agouti-Related Protein / Q000378:metabolism / Q000494:pharmacology; D000679:Amygdala / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics*; D059305:Diet, High-Fat; D004167:Diphtheria Toxin / Q000008:administration & dosage; D005215:Fasting; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism* / Q000473:pathology; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics*; D013238:Stereotaxic Techniques; D013495:Supraoptic Nucleus / Q000378:metabolism; D015431:Weight Loss
chemical_list: D054369:Agouti-Related Protein; D051792:Basic Helix-Loop-Helix Proteins; D004167:Diphtheria Toxin; D012097:Repressor Proteins; C515199:Agrp protein, mouse; C101750:Sim1 protein, mouse