TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neurons
Runping Wang, … , Mark W. Chapleau, François M. Abboud
Runping Wang, … , Mark W. Chapleau, François M. Abboud
Published March 7, 2019
Citation Information: JCI Insight. 2019;4(5):e122058. https://doi.org/10.1172/jci.insight.122058.
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Research Article Cell biology Metabolism

TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neurons

Abstract

The satiety effects and metabolic actions of cholecystokinin (CCK) have been recognized as potential therapeutic targets in obesity for decades. We identified a potentially novel Ca2+-activated chloride (Cl–) current (CaCC) that is induced by CCK in intestinal vagal afferents of nodose neurons. The CaCC subunit Anoctamin 2 (Ano2/TMEM16B) is the dominant contributor to this current. Its expression is reduced, as is CCK current activity in obese mice on a high-fat diet (HFD). Reduced expression of TMEM16B in the heterozygote KO of the channel in sensory neurons results in an obese phenotype with a loss of CCK sensitivity in intestinal nodose neurons, a loss of CCK-induced satiety, and metabolic changes, including decreased energy expenditure. The effect on energy expenditure is further supported by evidence in rats showing that CCK enhances sympathetic nerve activity and thermogenesis in brown adipose tissue, and these effects are abrogated by a HFD and vagotomy. Our findings reveal that Ano2/TMEM16B is a Ca2+-activated chloride channel in vagal afferents of nodose neurons and a major determinant of CCK-induced satiety, body weight control, and energy expenditure, making it a potential therapeutic target in obesity.

Authors

Runping Wang, Yongjun Lu, Michael Z. Cicha, Madhu V. Singh, Christopher J. Benson, Christopher J. Madden, Mark W. Chapleau, François M. Abboud

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Figure 5

Metabolic changes in Nav1.8 Cre;Ano2fl/WT (Ano2+/–) mice.

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Metabolic changes in Nav1.8 Cre;Ano2fl/WT (Ano2+/–) mice. (A) The percen...
(A) The percent body weight in Ano2+/+ vs. Ano2+/– mice is 15.6% ± 3.3% vs.18.4% ± 2.4% for fat mass, 65.0% ± 2.6% vs.61.1% ± 1.8% for lean mass and 0.267 ± 0.072 vs. 0.314 ± 0.048 for fat/lean mass ratio, respectively (Student’s t test, P > 0.05 for all). By excluding the 2 outliers of the 12 Ano2+/+ mice that had a percent fat mass that exceeded the mean by 3 SD, the calculated fat/lean mass ratio in this control (Ano2+/+) group decreased to 0.165 ± 0.026, making the increase in fat/lean mass ratio in Ano2+/– mice significantly greater statistically (Student’s t test, P < 0.05). (B) Food intake in control vs. Ano2+/– mice is 1.08 ± 0.20 vs.0.75 ± 0.08 g (P > 0.05) in light phase and 1.88 ± 0.14 g vs.1.84 ± 0.09 g (P > 0.05) in dark phase. The 24-hour cumulative food intake shows a significant decrease (right panel, P < 0.0001, 2-way ANOVA) mostly during the light phase and is associated with a decrease in locomotor activity. The dark phase (shaded) was between hours 6 p.m. and 6 a.m. (C) The energy expenditure of Ano2+/– mice is reduced in light and dark phases. The cumulative energy expenditure in Ano2+/– mice is significantly lower as shown during the light phase (unshaded; P < 0.0001, 2-way ANOVA). (D) The locomotor activity of Ano2+/– mice is reduced in light and dark phases. The cumulative locomotor activity is decreased in Ano2+/– mice through the 24-hour period (P < 0.0001, 2-way ANOVA). (E) The glucose tolerance test shows significantly lower glucose levels in the Ano2+/– mice at 30, 60, and 120 minutes after glucose injection (n = 12 mice in each group, P = 0.0103, 2-wayANOVA). (F) The insulin tolerance test shows no difference in glucose levels between control and Ano2+/– mice at 15, 60, and 120 minutes after insulin injection (n = 12 for Ano2+/+ and 13 for Ano2+/– mice, P > 0.05, 2-way ANOVA). Data are means ± SEM. Each dot or circle represents 1 mouse. Student’s t tests are applied in A and in the left and middle panels of B, C, and D; 2-way ANOVA are applied to right panels of B, C, and D. More values for locomotor activity, energy expenditure, and glucose and insulin tolerance are presented in Supplemental Table 1.