Role of brown adipose tissue in meal-induced thermogenesis and the involvement of the sympathetic nervous system

Individual variation in adaptive thermogenesis (AT) can potentially be
attributed to mitochondrial uncoupling in brown adipose tissue (BAT) and/or
skeletal muscle (SM). Mitochondrial uncoupling in these tissues may be of
metabolic significance, as well as to become pharmaceutically activated in
efforts to combat obesity. Recent studies have shown the presence of BAT in
human adults by exposing them to mild cold and subsequently measured them by
FDG PET-CT imaging. BAT may thus be considered as an organ of physiological and
pharmaceutical importance even in adults. Additionally, we recently showed that
mitochondrial uncoupling in human skeletal muscle tissue is related to adaptive
thermogenesis after mild cold exposure.
Next to mild cold exposure, diet also induces AT by increasing BAT activity,
probably wasting the excessive energy intake, as shown in animal overfeeding
studies. Moreover, several rat studies have shown that even a single meal can
stimulate brown adipose tissue activity mediated by the sympathetic nervous
system (SNS). Finally, overfeeding induced adaptive thermogenesis and cold
induced adaptive thermogenesis in humans seem to share common underlying
mechanisms, both involving the SNS. Therefore it is hypothesized that a single
meal is capable of increasing AT through mitochondrial uncoupling in BAT and
SM, mediated by the SNS. Furthermore, it is expected that these responses will
be blunted in obese people.

Examine the effects of a single meal on BAT activation and intrinsic
mitochondrial uncoupling in SM in lean and obese individuals, and define the
role of the SNS within this response.

Three experiments will be conducted per individual. The first experiment will
examine BAT activity (FDG PET-CT) after ingestion of a high caloric liquid meal
(high in carbohydrates), whereas the second after ß-adrenergic stimulation by
isoprenaline infusion. Finally, during the third experiment (positive control
experiment) BAT activity will be measured after exposure to mild cold for 2
hours. Furthermore, energy expenditure by means of indirect calorimetry will be
assessed and compared to BAT activity and to the intrinsic uncoupling capacity
in SM. Therefore, mitochondrial uncoupling will be studied in a muscle biopsy
taken prior to the experiment. Finally, body composition will be determined
with a DXA scan, and skin perfusion and relevant body temperatures will be
measured as well.

Each individual will undergo three experiments with a different intervention.
During the first experiment, the individual will receive a liquid meal
containing 60% of their daily required energy intake. The meal will consist of
nutridrink protein and nutrical, which is a protein rich and a carbohydrate
rich drink respectively. The macronutrient composition is as follows: 10%
protein, 78% carbohydrates, 12% fat.
The second experiment will consist of isoprenaline infusion in order to
stimulate the sympathetic nervous system. This will be applied in three
(incremental) doses (6,12 and 24 ng per kg fat free mass), of which each will
last 30 minutes. Moreover, half of each group will ingest 250 mg of acipimox
two hours before and at the onset of the experiment. This will supress
lipolysis resulting in lower FFA levels in the blood, subsequently stimulating
glucose usage.
Finally, the positive control experiment will consist of exposure to mild cold
(16 ºC) for two hours.

The isoprenaline infusion test contains relatively low doses (max 24 ng per kg
of body weight), which will not be a serious risk for the patient.
The absorbed radiation dose from a FDG PET-CT scan after administration of 50
MBq of 18F-FDG is 1.8 mSv, which is considered as a low risk.
Finally, participants will be measured for just three mornings in total.