brain where stretching is occurring, leading to changes in
gastrointestinal motility, movement of food through the
gastrointestinal tract and also feelings of fullness and satiety.
In the wall of the small intestine there are specialised
enteroendocrine cells that detect speciic nutrients. In response
they release peptides or hormones that affect appetite and play
a role in the control of blood glucose. Released hormones can
either enter the circulation or act directly on vagal afferent
nerves in the small intestine.
Enteroendocrine cells are also present in the stomach, but the
hormones released modulate the response to mechanical stretch
rather than having a direct effect on the nerves. For example,
ghrelin is an appetite-stimulating hormone produced by the
stomach. Ghrelin reduces the response of stretch-sensitive nerves
in the stomach, and thus reduces the satiety signals generated in
the stomach.
Vagal afferent nerves represent a highly plastic connection
between the gastrointestinal tract and the central nervous
system, responding to both nutrients and appetite-regulating
hormones. This plasticity is essential to ensure appropriate
functionality in the everyday control of food intake.
However, this system is extremely susceptible to disruption
by a high-fat diet and obesity. Our laboratory studies of obesity
in mice have shown that the responses of these nerves to
stretching of the stomach is signiicantly dampened in obesity
induced by a high-fat diet. As a result, the stomach needs to be
much more full to give the same feelings of satiety.
This is a common feature along the gastrointestinal tract.
The response of small intestinal nerves to certain gastroin-testinal hormones is also reduced in high fat diet-induced
obesity.
Reducing or delaying the satiety signal generated in the
gastrointestinal tract will delay the cessation of eating, thus
perpetuating the obese state. If we can understand the mech-
anisms behind these changes then perhaps we can target a
therapy to prevent the onset of obesity and the complications
associated with this disease.
The transient receptor potential vanilloid channel (TRPV1)
is best known as a mediator of noxious or painful stimuli. Acti-
vation of TRPV1 in pain-sensing nerves leads to painful burning
sensations. For example, activation of TRPV1 channels by
capsaicin, a component of hot chilli peppers, is responsible for
the hot burning sensation experienced when eating hot chillies.
However, TRPV1 also has physiological roles that aren’t
associated with pain, including a possible role in the regulation
of metabolism. It’s been suggested that targeted activation of
TRPV1 channels might provide a pharmacological therapy for
the treatment of obesity.
TRPV1 channels are expressed in the vagal afferent nerves
innervating the gastrointestinal tract. In mice that have been
genetically modiied so they have no TRPV1 channels, the
response of nerves to stretching of the stomach is signiicantly
reduced, indicating that TRPV1 channels play a role in satiety
signalling from the gut.
There is also an increase in daily food intake in these mice.
While this may be due to reduced satiety signalling from the
stomach, at present there is no direct evidence for this.
If these mice are then fed a high-fat diet there is no further22 | MAY 2016
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