Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling.
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.
Seo
Seongjin
S
Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa, IA 52242, USA.
Guo
Deng-Fu
DF
Bugge
Kevin
K
Morgan
Donald A
DA
Rahmouni
Kamal
K
Sheffield
Val C
VC
D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000097:blood / Q000378:metabolism*; D031204:Caloric Restriction; D002460:Cell Line; D056385:Group II Chaperonins; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology; D020738:Leptin / Q000097:blood; D053486:Melanocortins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism*; D054411:Receptors, Leptin / Q000378:metabolism*; D015398:Signal Transduction
C506281:BBS4 protein, mouse; C528012:Bbs2 protein, mouse; D020738:Leptin; D053486:Melanocortins; D008869:Microtubule-Associated Proteins; C506279:Mkks protein, mouse; D018832:Molecular Chaperones; D011506:Proteins; D054411:Receptors, Leptin; D011333:Pro-Opiomelanocortin; D056385:Group II Chaperonins