Journal article
TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neurons
JCI insight, Vol.4(5), e122058
03/07/2019
DOI: 10.1172/jci.insight.122058
PMCID: PMC6483506
PMID: 30843875
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 Ca
2+
-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 Ca
2+
-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.
CCK-induced activation of Ano2/TMEM16B in intestinal vagal afferents contributes to satiety and energy metabolism, and its reduction causes obesity.
Details
- Title: Subtitle
- TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neurons
- Creators
- Runping Wang - Department of Internal Medicine.Yongjun Lu - Department of Internal Medicine.Michael Z. Cicha - University of IowaMadhu V. Singh - University of IowaChristopher J. Benson - University of IowaChristopher J. Madden - Oregon Health & Science UniversityMark W. Chapleau - University of IowaFrançois M. Abboud - University of Iowa
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.4(5), e122058
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/jci.insight.122058
- PMID
- 30843875
- PMCID
- PMC6483506
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Grant note
- 1-13-BS-120 / ; R01-DK112198 / ; HL014388-42 / ; BX001414 / ; HL007121 / NHLBI
- Language
- English
- Date published
- 03/07/2019
- Academic Unit
- Molecular Physiology and Biophysics; Critical Care; Stead Family Department of Pediatrics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Nephrology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984297612902771
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