Abstract P323: TMEM16A and TMEM16B Contribute to Mice Cholecystokinin Response in Sex-Specific Manner

Abstract

High fat diet (HFD) leads to obesity and the metabolic syndrome. However, the effect are less pronounced in females than in males. We suggest that a gender difference is in their response to the satiety peptide Cholecystokinin (CCK). We previously reported that the Ca 2+ -activated Cl - channel (CaCC) subunit Ano2 /TMEM16B is essential for the CCK-induced current in intestinal nodose neurons in male mice, and is down regulated in obese mice fed on HFD. We hypothesize that the CCK-induced current in female mice is mediated predominantly by Ano1 /TMEM16A, the alternative subunit of TMEM16B. We studied the CCK-induced current in nodose neurons from female C57BL/6 mice using whole cell patch-clamp. We found that 10nM of CCK induces an inward current in these neurons with a current density averaging 13.4±2.5 pA/pF (n=7), and this current is inhibited to 3.1±1.2 pA/pF (n=7, p<0.01) by TMEM16A specific inhibitor T16A inhi-A01 . We further tested whether HFD which effectively suppressed the expression of TMEM16B in male mice, would also decrease TMEM16A in female mice. Our results show that the CCK-induced TMEM16A current in nodose neurons is not decreased in female, but tend to increase from 12.5±1.6 (n=10) in control to 17.4±4.1 pA/pF (n=11, p=0.298) in female mice fed on HFD. Concurrently the mRNA level of Ano1 in mice fed on HFD also show a trend to increase by 1.33±0.41 fold (n=2 pairs of mice, p=0.37) compared to mice on regular chow. Our findings indicate that activation of CCK-sensitive Ano1 /TMEM16A may partially protect female mice from HFD induced obesity and metabolic syndrome.