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Anoctamins are Determinants of Reduced Cholecystokinin Sensitivity of Vagal Afferents and Impaired Satiety in Obese Mice on High Fat Diet
Author(s) -
Lu Yongjun,
Wang Runping,
Cicha Michael,
Chapleau Mark,
Abboud Francois
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.806.1
Subject(s) - cholecystokinin , medicine , endocrinology , nodose ganglion , receptor , chemistry , vagus nerve , biology , stimulation
Anoctamin proteins (Ano1 & Ano2) are novel transmembrane proteins (TMEM16A & TMEM16B) that function as calcium‐activated chloride channels (CaCCs). Using patch‐clamping technique, we previously showed that the response of CaCCs to cholecystokinin (CCK) is significantly decreased in vagal sensory nodose neurons (VSNN) from mice on high fat diet (HFD). Here we define the molecular determinants of this impaired CCK response. Six weeks old C57BL/6 male mice were fed either HFD (60% fat) or a regular diet (control, 6.2% fat). At 4‐5 months the HFD mice were significantly heavier (41.4±4.7g, n=24) than control (28.4±3.6g, n=24, p<0.01). Nodose ganglia were removed under anesthesia. Expression of mRNA(qPCR) of CCKR (receptors) was slightly increased in ganglia from HFD (n=3) vs. control mice (n=3) (147±29% for CCKR A , p<0.05 and 117±22% for CCKR B , p>0.05). The CCKR A mRNA in individual intestinal nodose neurons labeled with DiO injected into the wall of the small intestine, confirmed that the expression of CCK receptors was not reduced by HFD. On the other hand the mRNA expression of Ano1 and Ano2 in ganglia from HFD mice was reduced to 59±9% and 29±7% (n=4, p<0.01) of the corresponding values in ganglia from control mice; and the corresponding proteins (immunofluorescence) were also reduced to 64±13% and 61±11% (n=3, p<0.05) of control values, respectively. We conclude that impaired CCK mediated satiety signaling in HFD‐induced obesity is caused by downregulation of the CCK‐ sensitive anoctamins and not by reduced CCK receptor expression in intestinal VSNN (HL14388).