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Bardet‐Biedl Syndrome (BBS) Proteins in AgRP Neurons Are Required for Energy Homeostasis
Author(s) -
Guo Deng Fu,
Rahmouni Kamal
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.750.3
Subject(s) - biology , neuropeptide y receptor , orexigenic , medicine , endocrinology , energy homeostasis , hypothalamus , neuropeptide , receptor , obesity
BBS is a pleiotropic autosomal recessive human disorder associated with several clinical features including obesity. We previously demonstrated that Bbs1 gene deletion from the nervous system caused obesity in mice highlighting the importance of neuronal BBS proteins for energy homeostasis. Here, we investigated the role of Bbs1 gene in the orexigenic agouti‐related peptide (AgRP) neurons present in the arcuate nucleus of the hypothalamus. We crossed Bbs1 fl/fl mice with AgRP Cre mice and confirmed Cre recombinase activity in AgRP neurons using td‐Tomato reporter mice. Interestingly, AgRP Cre /Bbs1 fl/fl mice developed obesity as indicated by the increased body weight (19% vs control littermates) and fat pad masses including brown adipose tissue, inguinal, perirenal and reproduction fats. Moreover, compared to male AgRP Cre /Bbs1 fl/fl mice, female AgRP Cre /Bbs1 fl/fl mice displayed profound obesity phenotype. Increased food intake contributed to the development of obesity in AgRP Cre /Bbs1 fl/fl mice. However, no change in hypothalamic genes regulating food intake (AgRP, proopiomelanocortin and neuropeptide Y) were detected in AgRP Cre /Bbs1 fl/fl mice relative to controls. The emerging importance of BBS proteins for the trafficking of receptors, particularly G protein‐coupled receptors (GPCR), led us to investigate the contribution of GPCR mistrafficking in AgRP neurons to the obesity phenotype. Using immunohistochemistry, we noticed that in hypothalamic neurons of wild type mice neuropeptide Y2 receptor (NPY2R) localize exclusively to cilia. Strikingly, deletion of the Bbs1 gene from AgRP neurons abolished the ciliary localization of NPY2R in these neurons, but not in other neuronal populations. Adenyl cyclase III, ciliary marker, was not affected by Bbs1 deletion suggesting that ciliary mistrafficking of NPY2R after Bbs1 ablation is specific. In HEK 293 cells, silencing the Bbs1 gene significantly decreased GFP‐tagged NPY2R trafficking to the plasma membrane. These findings demonstrate that BBS1 protein in AgRP neurons is involved in the regulation of energy homeostasis by controlling the trafficking of receptors such as NPY2R.