Effects of timing of food intake on glucose metabolism and the brain during a hypocaloric diet in obese subjects

The global occurrence of obesity has increased dramatically during the past
decade. Obesity is associated with increased morbidity and mortality explained
by the medical consequences of obesity, including type 2 diabetes mellitus and
cardiovascular disease. Treatment of obesity is difficult and often
unsuccessful because dietary restrictions frequently result in weight regain
after initial weight loss probably as a result of increased motivation to eat
and a rise in hunger and craving scores. The brain plays a central role in the
regulation of feeding behavior, and through energy restriction multiple
metabolic signals from peripheral organs will signal the brain to increase food
intake and thus modulate feeding behavior in addition to weight loss induced
changes in glucose metabolism. Within the brain, serotonin is an important
regulator of food intake and body weight. Extracellular serotonin
concentrations, available for receptor binding and serotonin signalling, is
regulated by the serotonin transporter (SERT). Interestingly, a negative
association between midbrain SERT and body weight has been shown and we
recently found a positive correlation between SERT and insulin sensitivity
(METC nr 10/292). Moreover, we recently reported a decrease in diencephalic
SERT upon a 6 weeks hypercaloric snacking diet in lean men (METC 10/247). Thus
serotonin might provide a link between the changes in feeding behavior and
glucose metabolism in periods of caloric excess and caloric restriction. The
adaptive serotonin response to these different states might predict body weight
gain or loss respectively as well the effects on glucose metabolism.
Besides the amount of consumed calories in relation to caloric need, recent
studies suggest a central role for the time of the day of food intake in
modulating body weight, appetite, and glucose metabolism and postulate that
consuming food at inappropriate times of the day contributes to the development
of obesity and insulin resistance. Importantly a recent study showed that in
obese subjects during a hypocaloric diet, consuming the majority of the
calories in the morning resulted in more profound and sustained weight loss in
the longer term compared to consuming the majority of calories during the
night. This suggests that during caloric restriction, timing of food intake is
an important determinant of long term weight loss. Since timing of food intake
is part of the circadian rhythm orchestrated by the brain, and serotonin is one
of the signaling neurotransmitters involved in circadian rhythm, changes in the
serotonergic system during hypocaloric conditions might explain these
differences.
We hypothesize that during a hypocaloric diet to promote weight loss in obese
subjects, consuming the majority of calories in the AM (i.e. at breakfast)
results in suppression of appetite and craving and improves insulin
sensitivity more compared to consuming the majority of calories in the PM (i.e.
at dinner).

To investigate whether in obese subjects meal timing during a hypocaloric diet
is related to the brain serotonergic system and insulin sensitivity as well as
to food-motivated behavior.

Open randomised controlled diet intervention study

Subjects will reduce their daily caloric intake with 50% for 4 weeks. Subjects
will be randomized into either a hypocaloric diet group where 15% of total kcal
have to be consumed with breakfast, 35% kcal with lunch and 50% kcal with
dinner or a hypocaloric diet group where 50% of kcal have to be consumed with
breakfast, 35% kcal with lunch and 15% kcal with dinner.

Total study duration is 4 weeks. Subjects will visit the AMC weekly and total
visit time will be about 34 hours. At study entry, subjects will be screened
for in- and exclusion criteria. Participations will follow a hypocaloric diet
for four weeks after randomization. The hypocaloric diet will be based on a 50%
caloric reduction which will result in a weight loss of approximately 7%. A
large number of short and long term health benefits can be achieved with even
5-10% weight loss such as beneficial effects on glucose metabolism and
components of the metabolic syndrome. Although dietary restriction often
results in initial weight loss, weight gain after weight loss represents one of
the major problems in therapeutic management of obesity. Adjusting the timing
of food intake could be a useful (and practical) strategy to maintain weight
loss and could have a long-term protective effect against the development of
the metabolic syndrome. Before and after four weeks on the hypercaloric diet, a
2-step hyperinsulinemic euglycemic clamp will be performed using stable
isotopes. Stable isotopes behave like their natural substrates and are
therefore not harmful. Blood samples will be obtained from an intravenous
cannula in a peripheral arm vein. Hypoglycemia during the hyperinsulinemic
clamps will not occur because plasma glucose will be measured bedside at
regular intervals. Total clamping time on one day will be 7 hours. Subjects
will undergo a SPECT-scan with the radioligand [123I]FP-CIT, administered
intravenously. At 2 and 3 hours after administration, a SPECT-scan of the brain
will be performed which takes about 40 minutes each, during which the
participant lies down on his back on the gamma camera bed. The day before
SPECT-scan and on the morning of the scan, subjects will be given potassium
iodide tablets to reduce uptake of the radioligand in the thyroid. [123I]FP-CIT
has a European (CPMP) registration, and it has been shown that it has no
serious side effects. As the dose equivalent per [123I]FP-CIT injection amounts
to 2.4 mSv (100MBq), the total dose equivalent of the participating subjects
will amount less than 10.0 mSv (222 MBq) (WHO category IIb). A pharmacological
MRI will be performed following serotonin challenge with a single and low dose
of the selective serotonin reuptake inhibitor (SSRI) citalopram (7.5mg
intravenously) to evaluate the serotonergic system. ASL is a non-invasive
cerebral blood flow imaging modality that uses magnetically labelled blood
water protons as an endogenous tracer of cerebral blood flow. Citalopram is the
only SSRI registered in the European Union for intravenous administration and a
well-tolerated treatment for severely depressed patients and for serotonin
modulation in MRI. For careful analysis of the SPECT-scan, a structural MRI of
the brain will be performed. In addition an MRI of the abdomen will be
performed to quantify visceral- and liver fat. The MRI-scans requires lying as
quiet as possible for 75 minutes.