title: Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype.
abstract: Agouti-related protein (AgRP) and neuropeptide Y (NPY) are colocalized in arcuate nucleus (arcuate) neurons implicated in the regulation of energy balance. Both AgRP and NPY stimulate food intake when administered into the third ventricle and are up-regulated in states of negative energy balance. However, mice with targeted deletion of either NPY or AgRP or both do not have major alterations in energy homeostasis. Using bacterial artificial chromosome (BAC) transgenesis we have targeted expression of a neurotoxic CAG expanded form of ataxin-3 to AgRP-expressing neurons in the arcuate. This resulted in a 47% loss of AgRP neurons by 16 weeks of age, a significantly reduced body weight, (wild-type mice (WT) 34.7+/-0.7 g vs. transgenic mice (Tg) 28.6+/-0.6 g, P<0.001), and reduced food intake (WT 5.0+/-0.2 vs. Tg 3.6+/-0.1 g per day, P<0.001). Transgenic mice had significantly reduced total body fat, plasma insulin, and increased brown adipose tissue UCP1 expression. Transgenic mice failed to respond to peripherally administered ghrelin but retained sensitivity to PYY 3-36. These data suggest that postembryonic partial loss of AgRP/NPY neurons leads to a lean, hypophagic phenotype.
authors.affiliation: Department of Metabolic Medicine, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: Gavin A
authors.initials: GA
authors.lastname: Bewick
authors.forename: James V
authors.initials: JV
authors.lastname: Gardiner
authors.forename: Waljit S
authors.initials: WS
authors.lastname: Dhillo
authors.forename: Aysha S
authors.initials: AS
authors.lastname: Kent
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: White
authors.forename: Zoe
authors.initials: Z
authors.lastname: Webster
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Ghatei
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Bloom
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D054369:Agouti-Related Protein; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015152:Blotting, Northern; D001823:Body Composition; D001835:Body Weight; D002352:Carrier Proteins / Q000378:metabolism; D022202:Chromosomes, Artificial, Bacterial / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D005091:Exons; D005247:Feeding Behavior; D017353:Gene Deletion; D054439:Ghrelin; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology; D017403:In Situ Hybridization; D007328:Insulin / Q000097:blood; D036341:Intercellular Signaling Peptides and Proteins; D007473:Ion Channels; D020738:Leptin / Q000097:blood; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins; D008957:Models, Genetic; D009474:Neurons / Q000378:metabolism*; D009478:Neuropeptide Y / Q000235:genetics* / Q000378:metabolism; D036361:Peptide Hormones / Q000378:metabolism; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D013851:Thinness / Q000235:genetics; D013997:Time Factors; D019076:Transgenes; D000071256:Uncoupling Protein 1; D015854:Up-Regulation
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D001786:Blood Glucose; D002352:Carrier Proteins; D018076:DNA, Complementary; D054439:Ghrelin; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009478:Neuropeptide Y; D036361:Peptide Hormones; D011506:Proteins; D012333:RNA, Messenger; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1