Diet-induced obesity (DIO) is primarily driven by the consumption of a high fat (HF) diet and is recognized as a major risk factor for the development of gastrointestinal (GI) motility complications, especially in the colon. Colonic motility is regulated by the division of the autonomic nervous system called the enteric nervous system (ENS). Despite high incidences of GI motility disorders in HF DIO, the role of enteric nervous system (ENS) in the development of these complications is unclear. The ultimate goal of this translational project was to understand how the consumption of a HF diet leads to impaired colon motility through effects on the cells controlling neuromuscular transmission. The etiology of obesity–induced colon motility disorders is multi-factorial and includes alterations to multiple cell types including enteric nerves and the GI smooth muscles. These cells communicate to control contraction and relaxation of smooth muscle via series of coordinated inhibitory and excitatory signaling mechanisms. Disturbances in these signaling mechanisms contribute to colon motility disorders. Therefore, it is crucial to identify in detail how neuromuscular transmission and smooth muscle excitability are regulated before the pathogenesis of HF diet associated colonic dysmotility can be studied. In the first part of this dissertation I studied the etiology of inhibitory neuromuscular transmission and smooth muscle excitability in the mouse distal colon. I found that inhibitory neuromuscular transmission is primarily mediated by ATP acting on P2Y1 receptors and nitric oxide (NO) diffusion on to the GI smooth muscle. These neurotransmitters act on the small conductance Ca2+-activated K+ (SK) channels and the Ca2+-activated Cl- (CaCCs) channels to produce IJPs in the mouse distal colon. In addition, I discovered that the large conductance Ca2+-activated K+ channels (β1BK channel) play a crucial role in regulation smooth muscle excitability by controlling smooth muscle action potential firing activity in the mouse distal colon. Next, I sought to determine how HF diet alters neuromuscular signaling and smooth muscle cell physiology. My results show that HF diet specifically disrupts NO mediated inhibitory neuromuscular transmission, SM relaxation and excitability leading to impaired colonic propulsive motility. Genetic KO of β1BK channel closely recapitulates HF diet induced impairments in the mouse distal colon. This suggests that compromised BK channel β1-subunit function/expression might play a role in mediating colonic dysmotility in obesity.
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