AG&M annual report 2018

AG&M Science Impressions 2018
The gut-brain axis in obesity
Richard IJzerman and Madelief Wijdeveld
The pathophysiological pathways that influence the
CNS regulation of food intake are the focus of Richard
IJzerman’s research group.
Obesity is a major public health problem due to its
pandemic occurrence and its association with adverse
consequences. Comparable to the role of CNS reward
and satiety responses in drug addiction, we and
others have demonstrated that obese individuals are
characterized by excessive eating due to altered central
nervous system (CNS) reward and satiety responses
to food.
To regulate food intake, signals arising from peripheral
organs involved in food intake, digestion and storage,
such as the gut, pancreas, and adipose tissue, convey
information on hunger and/or satiety to the CNS.
The ability of the gut to communicate with the CNS is
known as the gut–brain axis.
Hormonal gut-brain axis
Glucagon like peptide (GLP)-1 receptor agonists showed
positive results with regard to weight reduction in
humans. Previous studies have demonstrated that gutderived
GLP-1 is important in the regulation of feeding
by relaying meal-related information on nutritional
status to the brain. In order to study its specific effects
on neuronal activity in the brain, our group performed
various functional MRI studies where people were
exposed to both virtual and actual food stimuli. Various
studies performed by our group have demonstrated
that blocking the action of endogenous GLP-1 prevented
meal induced reductions in CNS activation in obese
T2DM patients. We also demonstrated by using fMRI
that GLP-1 receptor activation (using a GLP-1 receptor
agonist) acutely decreased food intake and also
decreased brain responses to visual food cues, which
may reduce food craving. In addition, GLP-1 receptor
activation acutely increased responses to actual food
intake, which may prevent overeating. After short term
treatment, patients using a GLP-1 receptor agonist
also showed decreased responses to food pictures.
Unfortunately, the CNS effects of the GLP-1 receptor
agonist disappeared after 12 weeks, and weight loss
with GLP-1 receptor agonists is on average only 3 kg.
Thus, in order to develop more powerful preventive
and therapeutic strategies, it is important to gain
further insight into pathways that influence central
reward and satiety circuits in the context of obesity.
Metabolic gut-brain axis
The last two decades have produced an avalanche of
studies revealing that intestinal microbiota provide a
substantial metabolic and physiological contribution
to energy homeostasis in the host. Obesity has been
associated with alterations in composition of intestinal
microbiota, and transfer of “obese” microbiota
can induce adiposity and hyperphagia in animals,
suggesting that gut microbiota may influence host
feeding behavior. The mechanisms underlying effects
of intestinal bacteria on host appetite in animal studies
are unknown, but may involve effects of short chain
fatty acids (SCFAs), in particular acetate. Acetate may
be an important player in the gut-brain axis. Acetate is
produced when non-digestible carbohydrates undergo
fermentation by the colonic microbiota. High amounts
of acetate reach the peripheral circulation and can
also directly affect host metabolism and function.
Acetate crosses the blood–brain barrier in rodents,
but the effects of acetate on food intake in animals
are controversial. In humans, acetate has been shown
to cross the blood–brain barrier and can be used as
a substrate in the brain. In addition, there is some
evidence that acetate increases short-term subjective
ratings of satiety and reduces body weight in humans.
In collaboration with Max Nieuwdorp, PhD student
Madelief Wijdeveld investigates the interaction
between the SCFA acetate and brain circuits involved
in the regulation of food intake in humans. Madelief
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