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Human Molecular Genetics Advance Access published online on January 15, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp031
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Requirement of Bardet-Biedl Syndrome Proteins for Leptin Receptor Signaling

Seongjin Seo1,2, Deng-Fu Guo3, Kevin Bugge1,2, Donald A. Morgan3, Kamal Rahmouni3,* and Val C. Sheffield1,2

1 Department of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA 2 Howard Hughes Medical Institute 3 Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA

* Correspondence to: Kamal Rahmouni, Ph.D., Department of Internal Medicine, University of Iowa Carver College of Medicine, 3135C MERF, Iowa City, IA, 52242, USA, e-mail: kamal-rahmouni{at}uiowa.edu, Tel: 319 353 5256, Fax: 319 353 5350

Received November 11, 2008; Revised January 14, 2009; Accepted January 14, 2009

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.


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