The effects of 4 weeks oral administration of omega-3 fatty acids on hepatic steatosis and insulin sensitivity in morbidly obese patients undergoing gastric bypass surgery.

Hepatic steatosis is characterized by excessive triglyceride accumulation in
the liver which is caused by either excessive import, diminished export and/or
impaired beta-oxidation of fatty acids. Without treatment, simple steatosis
(non-alcoholic fatty liver disease, NAFLD) may progress to an inflammatory
state (non-alcoholic steatohepatitis, NASH) and ultimately fibrosis, cirrhosis
and hepatocellular carcinoma (HCC). The prevalence of NAFLD in industrialized
populations ranges from 20-40%. NAFLD is directly linked to obesity/the
metabolic syndrome and with the epidemic growth of obesity, a higher incidence
of NAFLD is expected.
Weight loss is the most effective treatment strategy for hepatic steatosis.
Permanent weight loss in morbidly obese subjects can only be reached by
bariatric surgery. However, enlarged steatotic livers may complicate surgery as
in case of laparoscopic gastric bypass surgery it diminishes technical
maneuverability in the gastroesophageal area. In addition, steatotic livers
seem to be more vulnerable to complications caused by direct liver tissue
damage when the liver is mobilized or retracted during operation. Therefore it
may be of clinical benefit to reduce the degree of hepatic steatosis. In a rat
model of hepatic steatosis, we recently showed that supplementation of omega-3
fatty acids significantly reduced TG accumulation in the liver (Marsman et al,
submitted). Fatty acids are activators of some nuclear receptors involved in
beta-oxidation, but until now it is not completely unraveled whether and how
omega-3 fatty acid supplementation affects hepatic steatosis in humans.

The aim of this study is to evaluate the effect of supplementation of a high
oral dose of omega-3 fatty acids on hepatic steatosis and glucose metabolism
in morbidly obese patients undergoing laparoscopic Roux-Y gastric bypass
surgery (LRYGBP).

Randomized controlled intervention study.

Eucaloric diet with high dose omega-3 fatty acids (Supportan®) vs eucaloric
diet without omega-3 fatty acids (Fresubin®) 4 weeks prior to laparoscopic
Roux-Y gastic bypass surgery.

Biometric data such as waist circumference, BMI and blood pressure will be
measured. During surgery biopsies will be taken from visceral and abdominal
subcutaneous adipose tissue and the liver. The risks of bleeding from the
biopsy sites during the bariatric surgery procedure are very small because the
biopsy sites are completely visible to the surgeon and local hemostasis will be
checked. Subjects will visit the research unit weekly during the study; total
visit time will be about 34 hours. In addition an MRS of the liver will be
performed to quantify liver fat content. The MRS-scan requires lying still as
possible for 45 minutes. Subjects will undergo a 2-step hyperinsulinemic
euglycemic clamp using stable isotopes before and after the diet period to
study glucose metabolism. For the administration of the stable isotope, glucose
and insulin and for blood sampling, intravenous canules will be inserted in the
left and right antecubital vein. Stable isotopes are not harmful and
hypoglycaemia will not occur because glucose is monitored every 5 minutes.
Total clamping time on one day will be 7 hours.