Meal-regulated Substrate Metabolism, Influence of Obesity and IL-6

Meal-regulated Substrate Metabolism, Influence of Obesity and IL-6

The overall purpose of this explorative yet quantitative study project is to understand how blocking IL-6 signaling leads to the expansion of adipose tissue mass in humans in vivo. The aim is to gain in depth knowledge about how IL-6 receptor blockade affects human lipid, glucose and protein metabolism, specifically the uptake and storage of substrates from a meal vs. their utilization, hence the balance determining whether one gains or loses fat mass.

Lacking IL-6 signaling leads to an expansion of adipose tissue mass in rodents and humans. However, the underlying mechanisms have not been identified.This project aims to investigate the overall hypothesis that IL-6 receptor blockade changes substrate metabolism during postabsorptive and postprandial states to favor storage over mobilization of fat and to favor glucose over fat as a source for energy production. This hypothesis finds some support in the literature: Infusion of recombinant IL-6 into humans, leading to high concentrations of IL-6 in the circulation, stimulates lipolysis and free fatty acid oxidation.

Therefore, the investigators hypothesize that IL-6 receptor blockade impairs the mobilization of FFA from adipose tissue and impairs fat oxidation in skeletal muscle in the postabsorptive state. In the postprandial, state the investigators hypothesize that IL-6 receptor blockade reduces the insulin-induced uptake and deposition of fat by adipose tissue and skeletal muscle, therefore contributing to ectopic fat deposition in the liver.

In this study 12 lean and 12 obese male participants will be included. The participants will attend one screening visit and two study visits. The IL-6 receptor antibody tocilizumab will be infused on study visit 1.

Isotope dilution techniques, blood flow measurements, arterio-venous differences across adipose tissue and skeletal muscle, fat and skeletal muscle biopsies will be used to assess lipid, glucose and protein kinetics on a whole-body as well as fat and skeletal muscle level in the fasting state and after the ingestion of a liquid mixed-meal. Respiratory exchange ratio will be measured by indirect calorimetry.

Inclusion Criteria:

Healthy males:

• Age ≥ 18 years and ≤ 40 years
• BMI < 18 and > 25 kg/m2
• Healthy (based on screening)
• Stable body weight for 6 months

Obese males:

• Age ≥ 18 years and ≤ 40 years
• BMI ≥ 30 and ≤ 40 kg/m2
• Healthy (based on screening)
• Stable body weight for 6 months

Exclusion Criteria:

• Smoking
• Evidence of severe thyroid or heart disease, inflammatory diseases, current infection, liver disease (transaminases >2x upper normal range), kidney disease (creatinine >1.5 mg/dl), known immunosuppressive disease, corticosteroid use, regular NSAID or paracetamol usage, aspirin use >100 mg/d, history of carcinoma, history of tuberculosis, anemia (hematocrit <33%), WBC <2 x 10^3/ul, platelets <100 x 10^3/ul, bleeding disorders, obstructive pulmonary disease
• Femoral hernia, vascular prosthesis, vascular thrombosis
• Previous nerve damage, many previous femoral catheter installations