Abstract 415: Metabolic And Cardiovascular Effects Of Cilia Ablation From The Leptin Receptor-containing Neurons

Abstract

Genetic defects that cause ciliary dysfunction are associated with obesity and cardiovascular diseases in humans and animal models suggesting that functional cilia are important for metabolism and cardiovascular regulation. Cilia are membrane-bound, microtubular projections present on the surface of virtually all cell types including the neurons that control metabolic and cardiovascular functions such as those expressing the leptin receptor (LepRb). To examine the importance of cilia expressed in these neurons, we tested the effect of ablating cilia. For this, we generated mice lacking a key component of the intraflagellar transport (IFT) machinery, IFT88 protein, required for cilia formation, in the LepRb-containing neurons. Breeding ift88 flox mice with LepRb Cre mice created mice deficient in ift88 gene only in the LepRb positive neurons as indicated by the pattern of tdTomato reporter expression. Importantly, ift88 flox /LepRb Cre mice displayed an obesity phenotype as indicated by the increased (P<0.05) body weight (41±2 vs. 37±1. g in controls) and fat mass measured by MRI (11±2 vs. 5±1 g in controls) in 25 weeks old mice. We found that the obesity phenotype in ift88 flox /LepRb Cre mice is not due to an increase in food intake (3.03±0.25 vs. 2.96±0.29 g in controls). In contrast, energy expenditure was reduced in the ift88 flox /LepRb Cre mice as indicated by the decreased (P<0.05) O 2 consumption (1.71±0.1 vs. 2.01±0.08 mL/100g/min in controls) and heat production (5.07±0.4 vs. 5.98±0.27 kcal/kg/h in controls). Moreover, radiotelemetry measurement of core body temperature showed that ift88 flox /LepRb Cre mice had lower 24 h body temperature (36.7±0.2 vs. 37.2±0.2 o C in controls). These results indicate that low metabolic rate accounts for the development of obesity in ift88 flox /LepRb Cre mice. Next, we assessed the hemodynamic consequence of ablating the ift88 gene in LepRb positive neurons. However, mean arterial pressure and heart rate were not significantly different in the ift88 flox /LepRb Cre mice (106±7 mmHg and 635±17 bpm, respectively) compared to controls (110±4 mmHg and 679±15 bmp). These findings demonstrate that deletion of cilia in LepRb expressing neurons alter energy homeostasis, but not cardiovascular regulation.