title: Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway.
abstract: Hypothalamic feeding circuits are essential for the maintenance of energy balance. There have been intensive efforts to discover new biological molecules involved in these pathways. Here we report that central administration of clusterin, also called apolipoprotein J, causes anorexia, weight loss and activation of hypothalamic signal transduction-activated transcript-3 in mice. In contrast, inhibition of hypothalamic clusterin action results in increased food intake and body weight, leading to adiposity. These effects are likely mediated through the mutual actions of the low-density lipoprotein receptor-related protein-2, a potential receptor for clusterin, and the long-form leptin receptor. In response to clusterin, the low-density lipoprotein receptor-related protein-2 binding to long-form leptin receptor is greatly enhanced in cultured neuronal cells. Furthermore, long-form leptin receptor deficiency or hypothalamic low-density lipoprotein receptor-related protein-2 suppression in mice leads to impaired hypothalamic clusterin signalling and actions. Our study identifies the hypothalamic clusterin-low-density lipoprotein receptor-related protein-2 axis as a novel anorexigenic signalling pathway that is tightly coupled with long-form leptin receptor-mediated signalling.
authors.affiliation: Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Gil
authors.forename: Byung-Soo
authors.initials: BS
authors.lastname: Youn
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Byun
authors.forename: Hu
authors.initials: H
authors.lastname: Huang
authors.forename: Churl
authors.initials: C
authors.lastname: Namkoong
authors.forename: Pil-Geum
authors.initials: PG
authors.lastname: Jang
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Young-Hwan
authors.initials: YH
authors.lastname: Jo
authors.forename: Gil Myoung
authors.initials: GM
authors.lastname: Kang
authors.forename: Hyun-Kyong
authors.initials: HK
authors.lastname: Kim
authors.forename: Mi-Seon
authors.initials: MS
authors.lastname: Shin
authors.forename: Claus U
authors.initials: CU
authors.lastname: Pietrzik
authors.forename: Bonghee
authors.initials: B
authors.lastname: Lee
authors.forename: Young-Bum
authors.initials: YB
authors.lastname: Kim
authors.forename: Min-Seon
authors.initials: MS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000855:Anorexia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D051152:Clusterin / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D004822:Epididymis / Q000187:drug effects / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism*; D008297:Male; D051379:Mice; D009765:Obesity / Q000150:complications / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D054411:Receptors, Leptin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013217:Starvation / Q000378:metabolism
chemical_list: D051152:Clusterin; D020738:Leptin; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor