Bardet‐Biedl Syndrome (BBS) Proteins in POMC Neurons are Required for Energy Homeostasis

Abstract

BBS is a pleiotropic autosomal recessive human disorder associated with several clinical features including obesity. We previously demonstrated that Bbs1 gene deletion from the leptin receptor expressing cells caused obesity in mice highlighting the importance of neuronal BBS proteins for energy homeostasis. Here, we investigated the role of Bbs1 gene in the anorexigenic pro‐opiomelanocortin (POMC) neurons. We crossed Bbs1fl/fl mice with POMCCre mice and confirmed Cre recombinase activity in POMC cells of POMCCre/td‐Tomato reporter mice. Interestingly, POMCCre/Bbs1fl/fl mice developed obesity as indicated by the increased body weight (28%) relative to control animals. Both increased energy intake and decreased energy expenditure (as indicated by the decreased O2 consumption and heat production) contributed to the development of obesity. 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 in POMC 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 POMC neurons abolished the ciliary localization of NPY2R in these neurons, but not in other neuronal populations. Adenyl cyclase III 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 decreased NPY2R trafficking to the plasma membrane. These findings demonstrate that BBS1 in POMC cells is involved in the regulation of energy homeostasis by controlling the trafficking of receptors such as NPY2R.