Journal article
The BBSome Controls Energy Homeostasis by Mediating the Transport of the Leptin Receptor to the Plasma Membrane
PLoS genetics, Vol.12(2), pp.e1005890-e1005890
02/2016
DOI: 10.1371/journal.pgen.1005890
PMCID: PMC4771807
PMID: 26926121
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.
Details
- Title: Subtitle
- The BBSome Controls Energy Homeostasis by Mediating the Transport of the Leptin Receptor to the Plasma Membrane
- Creators
- Deng-Fu Guo - Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of AmericaHuxing Cui - Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of AmericaQihong Zhang - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of AmericaDonald A Morgan - Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of AmericaDaniel R Thedens - Department of Radiology, University of Iowa, Iowa City, Iowa, United States of AmericaDarryl Nishimura - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of AmericaJustin L Grobe - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, United States of AmericaVal C Sheffield - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of AmericaKamal Rahmouni - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, United States of America
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.12(2), pp.e1005890-e1005890
- DOI
- 10.1371/journal.pgen.1005890
- PMID
- 26926121
- PMCID
- PMC4771807
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7390
- eISSN
- 1553-7404
- Publisher
- Public Library Science; United States
- Grant note
- R01 EY011298 / NEI NIH HHS EY-017168 / NEI NIH HHS HL084207 / NHLBI NIH HHS EY-011298 / NEI NIH HHS R01 EY017168 / NEI NIH HHS R01 NS083543 / NINDS NIH HHS P01 HL084207 / NHLBI NIH HHS S10 RR025439 / NCRR NIH HHS 1 S10 RR025439-01 / NCRR NIH HHS
- Language
- English
- Date published
- 02/2016
- Academic Unit
- Radiology; Electrical and Computer Engineering; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine; Ophthalmology and Visual Sciences
- Record Identifier
- 9984040265802771
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