Abstract 415: Metabolic And Cardiovascular Effects Of Cilia Ablation From The Leptin Receptor-containing Neurons
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 ift88flox mice with LepRbCre mice created mice deficient in ift88 gene only in the LepRb positive neurons as indicated by the pattern of tdTomato reporter expression. Importantly, ift88flox/LepRbCre 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 ift88flox/LepRbCre 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 ift88flox/LepRbCre mice as indicated by the decreased (P<0.05) O2 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 ift88flox/LepRbCre mice had lower 24 h body temperature (36.7±0.2vs.37.2±0.2 oC in controls). These results indicate that low metabolic rate accounts for the development of obesity in ift88flox/LepRbCre 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 ift88flox/LepRbCre 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.
Author Disclosures: D.F. Guo: None. D.A. Morgan: None. J. Grobe: None. K. Rahmouni: None.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).
- © 2014 by American Heart Association, Inc.