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 (Chris) Madden, Mark W. Chapleau, François M. Abboud

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalJCI insight
Volume4
Issue number5
DOIs
StatePublished - Mar 7 2019

Fingerprint

Afferent Neurons
Cholecystokinin
Energy Metabolism
High Fat Diet
Obesity
Obese Mice
Chloride Channels
Brown Adipose Tissue
Thermogenesis
Vagotomy
Sensory Receptor Cells
Heterozygote
Chlorides
Body Weight
Phenotype
Neurons
Therapeutics

Keywords

  • Cell Biology
  • Chloride channels
  • Metabolism
  • Obesity

Cite this

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

In: JCI insight, Vol. 4, No. 5, 07.03.2019.

Research output: Contribution to journalArticle

Wang, Runping ; Lu, Yongjun ; Cicha, Michael Z. ; Singh, Madhu V. ; Benson, Christopher J. ; Madden, Christopher (Chris) ; Chapleau, Mark W. ; Abboud, François M. / TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neurons. In: JCI insight. 2019 ; Vol. 4, No. 5.
@article{e58369de3184432fa5ca9ded505c674c,
title = "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.",
keywords = "Cell Biology, Chloride channels, Metabolism, Obesity",
author = "Runping Wang and Yongjun Lu and Cicha, {Michael Z.} and Singh, {Madhu V.} and Benson, {Christopher J.} and Madden, {Christopher (Chris)} and Chapleau, {Mark W.} and Abboud, {Fran{\cc}ois M.}",
year = "2019",
month = "3",
day = "7",
doi = "10.1172/jci.insight.122058",
language = "English (US)",
volume = "4",
journal = "JCI insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "5",

}

TY - JOUR

T1 - TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neurons

AU - Wang, Runping

AU - Lu, Yongjun

AU - Cicha, Michael Z.

AU - Singh, Madhu V.

AU - Benson, Christopher J.

AU - Madden, Christopher (Chris)

AU - Chapleau, Mark W.

AU - Abboud, François M.

PY - 2019/3/7

Y1 - 2019/3/7

N2 - 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.

AB - 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.

KW - Cell Biology

KW - Chloride channels

KW - Metabolism

KW - Obesity

UR - http://www.scopus.com/inward/record.url?scp=85062591413&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062591413&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.122058

DO - 10.1172/jci.insight.122058

M3 - Article

C2 - 30843875

AN - SCOPUS:85062591413

VL - 4

JO - JCI insight

JF - JCI insight

SN - 2379-3708

IS - 5

ER -