title: The BBSome Controls Energy Homeostasis by Mediating the Transport of the Leptin Receptor to the Plasma Membrane.
abstract: Bardet-Biedl syndrome (BBS) is a highly pleiotropic autosomal recessive disorder associated with a wide range of phenotypes including obesity. However, the underlying mechanism remains unclear. Here, we show that neuronal BBSome is a critical determinant of energy balance through its role in the regulation of the trafficking of the long signaling form of the leptin receptor (LRb). Targeted disruption of the BBSome by deleting the Bbs1 gene from the nervous system causes obesity in mice, and this phenotype is reproduced by ablation of the Bbs1 gene selectively in the LRb-expressing cells, but not from adipocytes. Obesity developed as a consequence of both increased food intake and decreased energy expenditure in mice lacking the Bbs1 gene in LRb-expressing cells. Strikingly, the well-known role of BBS proteins in the regulation of ciliary formation and function is unlikely to account for the obesogenic effect of BBS1 loss as disruption of the intraflagellar transport (IFT) machinery required for ciliogenesis by deleting the Ift88 gene in LRb-expressing cells caused a marginal increase in body weight and adiposity. Instead, we demonstrate that silencing BBS proteins, but not IFT88, impair the trafficking of the LRb to the plasma membrane leading to central leptin resistance in a manner independent of obesity. Our data also demonstrate that postnatal deletion of the Bbs1 gene in the mediobasal hypothalamus can cause obesity in mice, arguing against an early neurodevelopmental origin of obesity in BBS. Our results depict a novel mechanism underlying energy imbalance and obesity in BBS with potential implications in common forms of human obesity.
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Deng-Fu
authors.initials: DF
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Huxing
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Qihong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Morgan
authors.affiliation: Department of Radiology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Thedens
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Darryl
authors.initials: D
authors.lastname: Nishimura
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America.|Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Grobe
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Val C
authors.initials: VC
authors.lastname: Sheffield
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America.|Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, United States of America.|Department of Internal Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Kamal
authors.initials: K
authors.lastname: Rahmouni
mesh_terms: D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology; D005260:Female; D007031:Hypothalamus / Q000502:physiology; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C464790:Bbs1 protein, human; C506280:Bbs1 protein, mouse; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D054411:Receptors, Leptin; C490898:Tg737Rpw protein, mouse; D025521:Tumor Suppressor Proteins