A systems biology approach to RESOLVE the molecular pathology of the hallmarks of patients with metabolic syndrome and its co-morbidities; Hypertriglyceridemia, low HDL-cholesterol and loss of glycemic control.

Metabolic syndrome in obesity is associated with disturbances in lipid and
glucose metabolism. Insulin resistance, glucose intolerance and dyslipidemia
co-occur in most cases and are diagnostic criteria for the metabolic syndrome.
The interactions between these perturbations in the metabolism of
HDL-cholesterol (HDL-C), triglycerides (TG), glucose as well as gut microbiota
composition are complex. There appear to be a broad variety between individuals
regarding the metabolic handling of excess calories. Resulting in metabolic
subtypes of obese persons, with obese subjects being either relatively insulin
sensitive with normal plasma lipids (metabolically healthy) or insulin
resistant with low HDL-C and high triglycerides (metabolically unhealthy).
Currently the most effective therapy to restore metabolic health, body weight
and reduce the risk for obesity-related morbidity and mortality in severely
obese patients is bariatric surgery. Roux-en Y gastric bypass (RYGB) has been
shown to ameliorate and even cure type 2 diabetes and dyslipidemia and to have
profound effects on the cardiovascular system. Unraveling the interaction
between caloric intake, body weight and glucose and lipid metabolism in these
subgroups of obese adults is of interest, because patho-physiological insight
will lead to novel treatment targets. We therefore propose to study the
interaction between metabolism of free fatty acids, triglycerides and glucose
in metabolically healthy and unhealthy morbidly obese men and women, before and
in the year following bariatric surgery.

To study the underlying mechanisms that connect the main pathological hallmarks
of the metabolic syndrome, i.e. high TG and loss of glycemic control in
morbidly obese patients undergoing bariatric surgery

A longitudinal cohort study.

Roux-en Y gastric bypass

Participants will be screened and informed about the study. Subjects will
report their diet-habits twice for 1 week prior to the studydays a diet-journal
on the internet. Shortly after, the subjects undergo an 2-step hyperinsulemic
euglycemic clamp and lipid- kinetics. During the lipid-kinetics subjects have
to drink heavy water and a palmitate shake and will receive a leucine and
glycerol bolus intravenous. These stable isotopes behave like their natural
substrates and are therefore not harmful. During the clamp and the lipid
kinetics two intravenous catheters will be placed to administer the stable
isotopes and for blood withdrawal. During the clamp plasma glucose will be
measured every 5 to 10 minutes to avoid severe hypoglycemia.
A MRS of the liver will be performed in order to quantify hepatic fat. The MR
spectroscopy studies have no risk. Subjects have to collect at two time points
24 hour stool samples to determine the microbiota composition.
During the clamp biopsies of a skeletal muscle and subcutaneous fat will be
taken and during bariatric surgery procedure biopsies of the liver and adipose
tissue will be taken. The risk of bleeding from the biopsy sites during the
bariatric surgery procedure is very low because the biopsy sites are completely
visible to the surgeon and local hemostasis will be checked twice. Moreover
bleeding disorders are an exclusion criterion.
Furthermore a pressure bandage will be applied over the incision of the
skeletal muscle biopsy. We therefore state that the scientific insight of our
findings will outweigh the minimal risks in this study.
All measurements with the exception of the surgical biopsies and the screening
visit will be repeated one year following bariatric surgery.