The effect of L-arginine on brown adipose tissue metabolism in South Asian and white Caucasian subjects

Within the academic hospital Maastricht and Maastricht University, the
departments of endocrinology, surgery, and human biology together with the
department of endocrinology at the Leiden University Medical Center study
metabolic diseases. Overweight and obesity are metabolic diseases that become
increasingly prevalent and can lead to the development of type 2 diabetes,
which may lead to several complications including cardiovascular disease. Since
2009, it has been known that brown adipose tissue (BAT) is important for energy
expenditure. BAT is a small organ which is mainly located along the great
vessels and is capable of rapidly burning fat towards heat. The more BAT a
subject has, the faster the metabolism is. People that are overweight have been
shown to have only little BAT. Perhaps the stimulation of BAT may be a novel
treatment to combat ovewreight and obesity. Interestingly, we have also shown
recently that not only people that are overweight, but also people from South
Asian descent have little BAT. The South Asian population has an increased risk
to develop overweight and type 2 diabetes as compared to white Caucasians and
the presence of little BAT from a young age on may contribute to their
increased risk. Mouse studies have shown that nitric oxide is important for the
formation of BAT. Interestingly, both white Caucasians with overweight and
healthy South Asian adolescents have been shown to have reduced release of
nitric oxide.

In this study, we will investigate the effect of increasing bioavailability of
nitric oxide in the body on BAT activity and metabolism and investigate whether
the efficacy of this strategy differs between South Asian and white Caucasian
subjects. We will study this by investigating the effect of suppletion of the
amino acid L-arginine, the precursor of nitric oxide.

In this study, we will investigate the influence of the amino acid L-arginine,
which enhances release of nitric oxide in the body, on BAT activity and
metabolism in healthy subjects with overweight. This will increase
understanding on the effect of L-arginine and nitric oxide on overweight and
BAT and hopefully, we will be more capable to treat overweight and obesity in
the future.

The study is a randomized, double blind placebo-controlled study with
cross-over design. Subjects will be randomized to receive first
L-arginine/placebo for 6 weeks, followed by a wash-out period of 4 weeks, and
then again 6 weeks of treatment with L-arginine/placebo. As the study is double
blind, the subject nor the investigator will know when the subject receives
which treatment.
At the end of both interventions, 2 study days will take place. On the first
day, the subject will arrive at 10.00 pm after a small breakfast at the
University and a cold-induced brown fat scan (PET-CT scan) will be made. This
study day will take approximately 5 hours. It is facultative to also undergo a
PET-MRI scan after the PET-CT scan. This takes approximately 45 min. In that
case, the first study day takes 6 hours. On the morning of day 2, the subject
will again arrive sober at the University and a muscle- and white fat biopsy
will be taken. The muscle biopsy will be taken from the big muscle in the upper
thy, and the fat biopsy from the subcutaneous abdomen. After the muscle and fat
biopsy, a glucose tolerance test will be performed. This second day will take
approximately 4.5 hours.

L-arginine (9 gram/day) and placebo. The study has a cross-over design and is
furthermore double blind. That means that the subject will first receive one of
these interventions for 6 weeks, followed by a 4-week 'wash-out' period and
then again 6 weeks of the other intervention. The subject does not know when he
receives L-arginine or placebo.

- There is a risk for the participant of getting a haematoma after the muscle
biopsy if the biopsy has not been executed well
- There is a risk for the participant of getting a heamatoma after placing the
catheter
- We do not expect that administration of L-arginine will be harmful to the
subjects in this study. The L-arginine is given in a physiological dose and
this dose has been given in previously published studies without reporting of
side effects by the subjects (36)
-Unexpected medical findings can potentially be detected
- We do not expect that administration of L-arginine will be harmful to the
subjects in this study. However, possible side effects may include: 1) enhanced
risk of bleeding (especially in people with bleeding disorders); 2)
hypoglycaemia (especially in people with type 2 diabetes or people that take
drugs, herbs or supplements that affect blood glucose); 3) hyperkalemia
(especially in people with liver or kidney function disorders); 4) hypotension
(especially in people that use anti-hypertensives) 5) bloating; diarrhea;
hematuria; increased inflammatory response (in people with asthma ); leg
restlessness, lower back pain; nausea, night sweats and flushing (with arginine
withdrawal); rash; reduction in hematocrit; stomach and intestine discomfort;
systemic acidosis.
- The effective dose of the PET/CT procedure and DXA-scan is 5.8 mSv, which is
considered a low risk. Due to participation in this study, the subjects cannot
participate in other research that involves radiation
- The PET-MRI scan is not associated with extra risk or radiation