Abstract
Abstract 020: Heterozygote Knockout of TMEM16B in Intestinal Vagal Afferents Causes Cholecystokinin Insensitivity and Obesity in Male but Not Female Mice
Hypertension (Dallas, Tex. 1979), Vol.70(suppl_1)
09/2017
DOI: 10.1161/hyp.70.suppl_1.020
Abstract
Cholecystokinin (CCK) is a well-known satiety peptide that inhibits food intake. The CCK induced satiety signal in intestinal vagal afferents is attenuated in mice on a High Fat Diet (HFD). We have shown that down regulation of a Ca
2+
-activated Cl
-
channel (CaCC) downstream of CCK receptors is responsible for the neuronal insensitivity to CCK. We also found that the CaCC subunit Ano2/TMEM16B is essential for the CCK-induced current in nodose neurons. In this study we tested the hypothesis that reduction of this subunit
in vivo
contributes to weight gain. One allele of the Ano2/TMEM16B was knocked out in sensory neurons by crossing the ano2
fl/
fl
mice with Nav1.8Cre mice to generate the Nav1.8Cre;ano2
fl
/wt
mice. The Cre negative littermates were used as control. We found that CCK-induced suppression of food intake is eliminated in male Nav1.8Cre;ano2
fl
/wt
mice. Food intake measured over 4 hours was 1.21±0.11g (n=5) in male wild type (wt) mice injected with saline and was reduced to 0.77±0.18 g (n=7, p<0.05) in mice injected with CCK-8 (3μg/kg). Those values were 0.63±0.15 g (n=6) in saline injected and 0.91±0.13 g (n=7, p>0.05) in CCK injected male Nav1.8Cre;ano2
fl
/wt
mice. However, the CCK injection did not affect food intake in either female wt or Nav1.8Cre;ano2
fl
/wt
mice. The male Nav1.8/ano2
fl/wt
mice were on the average 5.5g heavier than wt mice at 40 weeks of age (39.8±1.4 g, n=13 vs 34.3±1.4 g, n=14, p<0.01). Body weight of females was significantly lower than in males but was not different between wt and Nav1.8Cre;ano2
fl
/wt
mice (30.4±1.0 g, n=14 vs 28.5±1.0 g, n=11, p=0.20 respectively). Single cell mRNA level of Ano2 and CCK-induced TMEM16 currents in nodose neurons were reduced significantly in male Nav1.8Cre;ano2
fl/wt
mice compared to Cre negative controls, but such changes were not seen in female mice. We conclude that heterozygote knockout of Ano2/TMEM16B specifically in sensory neurons causes neuronal insensitivity to CCK and excessive weight gain in male but not female mice. Reduction of this subunit may contribute to the HFD induced obesity. The reason for the phenotype and allele expression variability between sexes is unclear.
Details
- Title: Subtitle
- Abstract 020: Heterozygote Knockout of TMEM16B in Intestinal Vagal Afferents Causes Cholecystokinin Insensitivity and Obesity in Male but Not Female Mice
- Creators
- Runping Wang - University of IowaYongjun Lu - University of IowaMichael Z Cicha - University of IowaChristopher J Benson - University of IowaMark W Chapleau - University of IowaFrancois M Abboud - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Hypertension (Dallas, Tex. 1979), Vol.70(suppl_1)
- DOI
- 10.1161/hyp.70.suppl_1.020
- ISSN
- 0194-911X
- eISSN
- 1524-4563
- Language
- English
- Date published
- 09/2017
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine; Nephrology; Stead Family Department of Pediatrics; Molecular Physiology and Biophysics; Neuroscience and Pharmacology; Critical Care
- Record Identifier
- 9984302996602771
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