Abstract 083: Metabolic and Cardiovascular Effects of BBS1 Ablation From the POMC-containing Neurons

Abstract

Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive disorder associated with several features including obesity and hypertension. Deletion of Bbs genes globally, in the nervous system or in the leptin receptor-expressing cells recapitulated many of the BBS phenotypes including obesity and hypertension. Here, we assessed the effect of ablating the Bbs1 gene from the neurons expressing proopiomelanocortin (POMC) neurons. Breeding Bbs1 flox mice with POMC Cre mice created mice deficient in Bbs1 gene only in the POMC-positive neurons (visualized by tdTomato expression). Importantly, POMC Cre /Bbs1 fl/fl mice display an obesity phenotype as indicated by the increased (P<0.05) body weight (48.6±1.7 vs 34.9±0.8 g in controls) and fat pads (3.3±0.3 vs. 0.7±1.1 g for inguinal fat, 2.1±0.2 vs. 0.4±0.05 g for perirenal fat, 3.3±0.3 vs. 0.8±0.3 g for reproduction fat and 0.4±0.02 vs. 0.2±0.02 g for brow fat) associated with increased (P<0.05) food intake (3.79.±0.14 vs. 2.97±0.15 g in controls) in 25 weeks old mice. POMC Cre /Bbs1 fl/fl mice displayed decreased (P<0.05) O 2 consumption (2.6±0.03 vs. 3±0.04 mL O 2 /100g/min in controls) and heat production (8.0±0.09 vs. 9.2±0.13 kcal/kg/hr in controls). These results indicate that hyperphagia and decreased energy expenditure contribute to the development of obesity in POMC Cre /Bbs1 fl/fl mice. Next, we assessed the consequence on arterial pressure (AP) and sympathetic nerve activity (SNA) of ablating the Bbs1 gene from POMC neurons. Interestingly, deletion of the Bbs1 gene in POMC neurons did not recapitulate the hypertension phenotype of BBS as indicated by the slight, but not significant increase in mean AP (116±4.7 vs 109±6.1 mmHg in controls). However, conscious renal SNA was significantly higher in POMC Cre /Bbs1 fl/fl mice relative to controls (132.4±11 vs 74.3±4.2 spikes/sec, P<0.05). Finally, the depressor effect of ganglionic blockade (hexamethonium) was exaggerated in POMC Cre /Bbs1 fl/fl mice (-68.6±4.4 vs -45.2±9.4 mmHg in control, P=0.017). These findings demonstrate that Bbs1 gene in the POMC neurons is critical for energy homeostasis, but not for arterial pressure regulation.