Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 311, Issue 2, Pages G210-G220Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00085.2016
Keywords
enteric nervous system; large conductance calcium-activated K+ channel; gastrointestinal motility; obesity
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [094932]
- Crohn's and Colitis Foundation of America (CCFA)
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We tested the hypothesis that colonic enteric neurotransmission and smooth muscle cell (SMC) function are altered in mice fed a high-fat diet (HFD). We used wild-type (WT) mice and mice lacking the beta(1)-subunit of the BK channel (BK beta(-/-)(1)). WT mice fed a HFD had increased myenteric plexus oxidative stress, a 28% decrease in nitrergic neurons, and a 20% decrease in basal nitric oxide (NO) levels. Circular muscle inhibitory junction potentials (IJPs) were reduced in HFD WT mice. The NO synthase inhibitor nitro-L-arginine (NLA) was less effective at inhibiting relaxations in HFD compared with control diet (CD) WT mice (11 vs. 37%, P < 0.05). SMCs from HFD WT mice had depolarized membrane potentials (-47 +/- 2 mV) and continuous action potential firing compared with CD WT mice (-53 +/- 2 mV, P < 0.05), which showed rhythmic firing. SMCs from HFD or CD fed BK beta(-/-)(1) mice fired action potentials continuously. NLA depolarized membrane potential and caused continuous firing only in SMCs from CD WT mice. Sodium nitroprusside (NO donor) hyperpolarized membrane potential and changed continuous to rhythmic action potential firing in SMCs from HFD WT and BK beta(-/-)(1) mice. Migrating motor complexes were disrupted in colons from BK beta(-/-)(1) mice and HFD WT mice. BK channel alpha-subunit protein and beta(1)-subunit mRNA expression were similar in CD and HFD WT mice. We conclude that HFD-induced obesity disrupts inhibitory neuromuscular transmission, SMC excitability, and colonic motility by promoting oxidative stress, loss of nitrergic neurons, and SMC BK channel dysfunction.
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