TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neurons
Runping Wang, Yongjun Lu, Michael Z. Cicha, Madhu V. Singh, Christopher J. Benson, Christopher J. Madden, Mark W. Chapleau, François M. Abboud
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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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 6

CCK-8 induces thermogenesis in rats fed on control but not in rats fed HFD diet or rats with vagotomy.

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CCK-8 induces thermogenesis in rats fed on control but not in rats fed H...
(A–C) The thermogenic responses of individual rats to 2 consecutive i.v. doses of CCK-8 (0.5 μg/kg and 5.0 μg/kg) recorded over a period of 50 minutes. The responses include 3 stimulatory effects of CCK, represented in each panel as increases in brown adipose tissue (BAT) sympathetic nerve activity (SNA root mean square [rms]) in the top tracing, BAT temperature (TBAT) in the middle, and expired carbon dioxide (Exp. CO2 %) in the lower tracing. (A) Pronounced dose-dependent increases in BAT SNA, TBAT, and Exp. CO2 in a rat on the control diet. (B) These responses are eliminated in a rat on the HFD. (C) These responses are eliminated in a vagotomized rat on the control diet. SNA amplitude, shown in red, was calculated as the rms value. The black scale bars to the right of the SNA tracings represent 20 μV in A, 100 μV in B, and 200 μV in C. (D) The 6 graphs in D show group data of the time course of the responses to each of the 2 doses of CCK over a 20-minute period. In each graph, the rats on the control diet (n = 6; filled circles) are compared with rats on the HFD (n = 5; open circles) and to vagotomized rats on the control diet (n = 5; filled triangles). Data are means ± SEM. Each symbol represents the mean value over 30 seconds. Student’s t tests were used to compare the 20-minute time point after each CCK injection between rats on the control diet and rats on the HFD. The pronounced increases in BAT SNA, TBAT, and Exp. CO2 seen with CCK-8 on the control diet were eliminated on the HFD (*P < 0.05). Similarly, vagotomy eliminated SNA and ΔTBAT and suppressed ΔExp. CO2 responses.