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

Summary: 
      The aim of the study is to investigate the effects of blocking IL-6 signaling with
      tocilizumab on lipid, glucose and protein metabolism during rest and exercise in healthy and
      obese humans.

      Interleukin-6 is a molecule produced by a variety of cells and impacts on energy metabolism
      during fasting and fed conditions. Systemic IL-6 levels are low but increase acutely in
      response to fasting, exercise and infection, and also chronically in response to obesity and
      other conditions of lowgrade inflammation.Our recent human intervention study showed that
      IL-6 receptor blockade prevents exercise training from reducing visceral fat mass.

      Whether IL-6 receptor blockade directly regulates lipolysis and/or lipid oxidation in humans
      is however unclear. Therefore, this study will be performed to investigate the physiological
      role of IL-6 on lipid, glucose and protein metabolism in humans.
    

Detailed description: 
      The aim of the study is to assess changes in substrate kinetics, that is, lipolytic rate,
      rate of appearance and disappearance of free fatty acids, fatty acid oxidation, glucose rate
      of appearance and disappearance and protein synthesis and degradation during rest and
      exercise with and without IL-6 receptor blockade. We will assess the acute effects of
      blocking IL-6 as well as the long-term consequences of IL-6 receptor blockade on all the
      above parameters.

      Overall, we hypothesize that blocking IL-6 changes substrate kinetics. More specifically we
      hypothesize that blocking IL-6 reduces the appearance of free fatty acids, reduces the
      lipolytic rate and lipid oxidation. We hypothesize that the consequences of blocking IL-6
      will be observed during resting and exercising conditions and both immediately and longterm
      after IL-6 receptor blockade. We hypothesize that IL-6 receptor blockade results in an
      increased respiratory exchange ratio (RER) and thus increased reliance on glucose as
      substrate.

      In this study 10 healthy males and 10 obese males will be included. Subjects will be infused
      with saline on 2 of the study days and tocilizumab on 1 of the study days.

      Isotope dilution techniques with [6,6-2H2]Glucose, [1,1,2,3,3-D5]glycerol,
      K-[U-13C16]palmitate, L-[ring-D5]phenylalanine, L-[D2]tyrosine will be applied to assess
      lipid, glucose and protein kinetics. Respiratory exchange ratio will be measured by indirect
      calorimetry. The BORG scale will be used to assess the perceived exertion during exercise.
    

Intervention name(s): Tocilizumab infusion; Saline 0.9%
Intervention type(s): Drug; Drug
Intervention description(s): Tocilizumab (8mg/kg body weight diluted to 100 ml NaCl 0.9%) will be infused over 1 hour; 100 ml NaCl 0.9% will be infused over 1 hour
Other intervention name(s): RoActemra; Saline
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 three study visits/study days. the Subjects will be infused with saline (placebo) on two of the study days and tocilizumab on one of the study days.
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Interleukin-6; Tocilizumab; Exercise; Substrate Metabolism; Lipolysis