Meal-regulated Substrate Metabolism, Influence of Obesity and IL-6
Condition: Obesity; Healthy
MeSH terms: Obesity
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Tocilizumab; Saline 0.9%
Intervention type(s): Drug; Drug
Intervention description(s): Baseline: Tocilizumab (infusion of 8 mg/kg bodyweight or a maximum of 800 mg) will be infused over 60 minutes at the end for the study day, therefore study visit 1 (study day 1) measurements are baseline.; Participants are under influence of tocilizumab since the effect of the drug will last for 4 weeks. Participants will be infused with saline at study visit 2 (study day 21). Placebo to tocilizumab will be saline (NaCl 0.9%) as tocilizumab is a colorless solution and has to be diluted with NaCl 0.9% prior to administration
Other intervention name(s): RoActemra
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Intervention model description: The study is designed in a placebo-controlled crossover manner, consisting of a screening visit and two study visits. Due to the 4-week wash out period of the IL-6 receptor antibody tocilizumab, the order of study visits will be identical in all subjects; hence, study visits will not be randomized. Subjects will be infused with tocilizumab at the end of study visit 1. This will allow us to study the effect of tocilizumab on study visit 2.
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Interleukin-6; Tocilizumab; Postprandial; Postabsorptive; Substrate metabolism; Fat metabolism; Glucose metabolism; Protein metabolism; Isotope dilution technique