Abstract MP55: Bardet-biedl Syndrome 3 Gene In Pomc Neurons Regulates Glucose Homeostasis And Baroreflex Sensitivity

Abstract

Bardet-Biedl syndrome (BBS) proteins have emerged as critical regulators of various physiological functions including energy and glucose homeostasis, autonomic function and blood pressure. BBS3 protein is a cilia related protein that mediates the ciliary localization of the BBSome, a protein complex composed of eight BBS protein. Consistent with this, we found that BBS3 gene knockout in human RPE1 cells disrupt the ciliary localization of BBS2 and BBS9 proteins, indicating a loss of BBSome-mediated cargo trafficking to cilia. We previously demonstrated that disruption of the BBSome through Bbs1 gene deletion in the anorexigenic pro-opiomelanocortin (POMC) neurons altered energy homeostasis and sympathetic nerve traffic. However, the significance of BBS3-mediated ciliary localization of the BBSome in POMC neurons is not clear. To address this, we investigated the consequence of Bbs3 gene deletion in POMC neurons . We generated mice lacking the Bbs3 gene in POMC neurons by crossing Bbs3 fl/fl mice with mice expressing inducible Cre in POMC neurons (POMC ERCre ). To visualize Cre recombinase we further crossed POMC ERCre /Bbs3 fl/fl mice with tdTomato reporter mice. To induce Cre expression tamoxifen (75 mg/kg for 5 days) was injected at 6 weeks of age. Interestingly, both male and female POMC ERCre /Bbs3 fl/fl mice did not develop obesity as indicated by the lack of difference in body weight (male 28.1 + 0.5 vs 28.3 + 1.2g, female 21.9 + 0.7 vs 21.4 + 0.5g), fat mass (male 2.9 + .0.4 vs 3.4 + 0.5g, female 2.7 + .3 vs 2.3 + 0.2g) and weight of white and brown fat pads. Insulin and glucose tolerance tests revealed that POMC ERCre /Bbs3 fl/fl mice have glucose intolerance, whereas insulin sensitivity was normal. Blood pressure and renal SNA were comparable between POMC ERCre /Bbs3 fl/fl and control mice measured in the conscious state. In contrast, measurement of renal SNA response to changes in arterial pressure evoked by infusion of sodium nitroprusside and phenylephrine showed reduced baroreflex sensitivity in POMC ERCre /Bbs3 fl/fl mice. These findings demonstrate that POMC neuron BBS3, that mediate cargo transport to cilia, is not necessary for the regulation of energy homeostasis, but is involved in the regulation of glucose homeostasis and baroreflex sensitivity.