The effect of Oral BUtyrate on human Glucose and brownfAT metabolism

Brown adipose tissue (BAT) is thought to be involved in human metabolism,
however the mechanisms by which this adipose tissue is activated remain to be
elucidated. Recent data in diabetic mice have suggested that intestinal
microbiota and their product butyrate have effect on weight, glucose metabolism
and potentially activation of BAT. Since oral butyrate treatment is safe and
has been given (in identical dosages as used in this study) to humans
previously, we will now aim to perform a small intervention in healthy lean and
obese, insulin resistant male subjects to study the effect of 4 gram of oral
butyrate supplementation during 1 month on glucose metabolism and BAT
activation.

Primary objective: To investigate whether butyrate influences the metabolic
activity of BAT (as assessed with a FDG-PET CT scan) in relation to hepatic and
peripheral insulin sensitivity (2H2-glucose and [1,1,2,3,3-2H5]glycerol based
two step hyperinsulinemic normoglycemic clamp).
Secondary Objectives: 1) To determine whether differences in resting energy
expenditure during thermoneutral conditions correlate with the metabolic BAT
activity before and after butyrate treatment. 2) To determine if fecal
gutmicrobiota and fecal energy excretion (triglycerides) are altered upon oral
butyrate treatment. 3) Changes in expression of genes involved in insulin
phosphorylation signalling pathways, inflammation and lipid synthesis in
subcutaneous fat upon oral butyrate supplementation.

Intervention trial

A total of 20 subjects will be included in this study. Healthy lean male
volunteers (N=10, age >18 years, BMI 19-25 kg/m2) and obese insulin resistant
male volunteers (n=10, age >18 years, BMI>25) will be recruited and tested for
BAT activity and insulin sensitivity before and after oral butyrate treatment.
The volunteers will be recruited by advertisement in local papers and internet
(via social media), covering the direct surroundings of our clinic (Amsterdam).

Included subjects will visit the AMC hospital on 5 occasions over a time trace
of 5 weeks. Total amount of blood that is drawn is 240cc. The resulting dose
from the radioactive tracers and the imaging procedures is 10.0 mSv. Although
no side effects have been reported in previous trials, subjects can encounter
potential side effects of the sodiumbutyrate treatment. There is no benefit for
the volunteers, but this research will provide insight into the mechanism of
brown fat activation in relation to insulin sensitivity, which may help us to
develop methods to combat obesity and insulin resistance.