Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling

Seongjin Seo; Deng-Fu Guo; Kevin Bugge; Donald A Morgan; Kamal Rahmouni; Val C Sheffield

doi:10.1093/hmg/ddp031

Back

Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling

Journal article

Open access

Peer reviewed

Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling

Seongjin Seo, Deng-Fu Guo, Kevin Bugge, Donald A Morgan, Kamal Rahmouni and Val C Sheffield

Human molecular genetics, Vol.18(7), pp.1323-1331

04/01/2009

DOI: 10.1093/hmg/ddp031

PMCID: PMC2655773

PMID: 19150989

Files and links (1)

url

https://doi.org/10.1093/hmg/ddp031View

Published (Version of record) Open Access

Abstract

Obesity is a major public health problem in most developed countries and a major risk factor for diabetes and cardiovascular disease. Emerging evidence indicates that ciliary dysfunction can contribute to human obesity but the underlying molecular and cellular mechanisms are unknown. Bardet-Biedl syndrome (BBS) is a genetically heterogeneous human obesity syndrome associated with ciliary dysfunction. BBS proteins are thought to play a role in cilia function and intracellular protein/vesicle trafficking. Here, we show that BBS proteins are required for leptin receptor (LepR) signaling in the hypothalamus. We found that Bbs2(-/-), Bbs4(-/-) and Bbs6(-/-) mice are resistant to the action of leptin to reduce body weight and food intake regardless of serum leptin levels and obesity. In addition, activation of hypothalamic STAT3 by leptin is significantly decreased in Bbs2(-/-), Bbs4(-/-) and Bbs6(-/-) mice. In contrast, downstream melanocortin receptor signaling is unaffected, indicating that LepR signaling is specifically impaired in Bbs2(-/-), Bbs4(-/-) and Bbs6(-/-) mice. Impaired LepR signaling in BBS mice was associated with decreased Pomc gene expression. Furthermore, we found that BBS1 protein physically interacts with the LepR and that loss of BBS proteins perturbs LepR trafficking. Our data indicate that BBS proteins mediate LepR trafficking and that impaired LepR signaling underlies energy imbalance in BBS. These findings represent a novel mechanism for leptin resistance and obesity.

Cell Line

Neurons - pathology

Molecular Chaperones - metabolism

Bardet-Biedl Syndrome - metabolism

Signal Transduction

Caloric Restriction

Melanocortins - metabolism

Microtubule-Associated Proteins - metabolism

Humans

Hypothalamus - pathology

Group II Chaperonins

Mice, Knockout

Protein Transport

Pro-Opiomelanocortin - metabolism

Animals

Hypothalamus - metabolism

Leptin - blood

Proteins - metabolism

Protein Binding

Mice

Neurons - metabolism

Receptors, Leptin - metabolism

Bardet-Biedl Syndrome - blood

Details

Title: Subtitle: Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling
Creators: Seongjin Seo - Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa, IA 52242, USA
Deng-Fu Guo
Kevin Bugge
Donald A Morgan
Kamal Rahmouni
Val C Sheffield
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.18(7), pp.1323-1331
DOI: 10.1093/hmg/ddp031
PMID: 19150989
PMCID: PMC2655773
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: England
Grant note: EY017168 / NEI NIH HHS HL084207 / NHLBI NIH HHS Howard Hughes Medical Institute EY011298 / NEI NIH HHS
Language: English
Date published: 04/01/2009
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Neuroscience and Pharmacology; Internal Medicine; Ophthalmology and Visual Sciences
Record Identifier: 9983980073602771

Metrics

31 Record Views

253 Times Cited - Web of Science

See more details